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Pharmacology Quiz

Antidepressants

Antidepressants are drugs that increase the availability of monoamine neurotransmitters, mainly serotonin and noradrenaline, at central synapses. These notes cover the monoamine hypothesis and the delay to clinical effect, each major drug class with its mechanism, named examples and adverse effects, the interactions that matter most in practice (serotonin syndrome, the tyramine reaction, discontinuation syndrome), the drugs of choice in common clinical situations, and the safety warnings examiners expect you to know. A 20-question practice set follows.

Basis of Action and General Principles

The monoamine hypothesis holds that depression is associated with reduced serotonergic and noradrenergic transmission, and every current antidepressant raises monoamine levels in the synaptic cleft. Levels rise within hours, but symptoms improve only after two to four weeks and full response may take six to eight weeks, so the therapeutic effect is attributed to slower adaptive changes such as receptor downregulation, increased brain-derived neurotrophic factor and hippocampal neuroplasticity rather than to the acute rise in transmitter itself.

  • Three ways of raising monoamines: blocking reuptake transporters, blocking presynaptic autoreceptors, or inhibiting the enzyme monoamine oxidase that degrades them.
  • Onset of mood improvement takes 2 to 4 weeks; an adequate trial before declaring failure is 4 to 6 weeks at a therapeutic dose.
  • Somatic symptoms such as sleep and appetite often improve before mood, which is one reason suicide risk can transiently rise early in treatment as energy returns before hopelessness lifts.
  • After a first episode, treatment continues for at least 6 to 12 months after remission to prevent relapse; recurrent illness may need indefinite treatment.
  • Antidepressants must not be stopped abruptly; taper to avoid discontinuation syndrome.
  • All antidepressants carry a boxed warning for increased suicidal thinking and behaviour in children, adolescents and young adults up to about age 24.

Selective Serotonin Reuptake Inhibitors and SNRIs

Selective serotonin reuptake inhibitors are first-line for major depressive disorder and most anxiety disorders because they are as effective as older agents but far safer in overdose. They block the serotonin transporter, leaving more serotonin in the cleft. Serotonin-noradrenaline reuptake inhibitors block both the serotonin and the noradrenaline transporters.

  • SSRIs: fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine.
  • Common SSRI adverse effects: nausea and gastrointestinal upset (usually settles), headache, insomnia or somnolence, sexual dysfunction (very common and persistent), weight change, and hyponatraemia from the syndrome of inappropriate antidiuretic hormone secretion, especially in the elderly.
  • Fluoxetine has the longest half-life (its active metabolite norfluoxetine lasts days), so it is least likely to cause discontinuation syndrome; paroxetine has the shortest half-life and the most anticholinergic effect, so it causes the worst discontinuation symptoms and is avoided in pregnancy.
  • Citalopram causes dose-dependent QT prolongation, so the maximum dose is restricted, particularly over age 60.
  • Sertraline is often preferred after myocardial infarction and in breastfeeding because of favourable safety data.
  • SNRIs: venlafaxine, desvenlafaxine, duloxetine, levomilnacipran. Venlafaxine is serotonergic at low dose and adds noradrenergic action at higher dose, where it can raise blood pressure.
  • Duloxetine is also licensed for diabetic peripheral neuropathic pain and fibromyalgia; it is avoided in significant hepatic impairment and heavy alcohol use.
  • SSRIs increase bleeding risk, particularly gastrointestinal bleeding when combined with non-steroidal anti-inflammatory drugs or anticoagulants, because platelets depend on serotonin uptake for aggregation.

Tricyclics, Monoamine Oxidase Inhibitors and Atypical Agents

Tricyclic antidepressants and monoamine oxidase inhibitors are as effective as newer drugs but are second or third line because of toxicity. Tricyclics are dangerous in overdose and monoamine oxidase inhibitors carry serious food and drug interactions. The atypical agents are used to avoid specific side effects such as sexual dysfunction or insomnia.

  • Tricyclics: amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin. They block serotonin and noradrenaline reuptake but also block muscarinic, histamine H1 and alpha 1 receptors, which explains most of their side effects.
  • Tricyclic side effects: dry mouth, constipation, urinary retention and blurred vision (antimuscarinic), sedation and weight gain (H1 blockade), postural hypotension (alpha 1 blockade).
  • Tricyclic overdose is a medical emergency with the three Cs: coma, convulsions and cardiotoxicity. Sodium channel blockade widens the QRS complex; treatment is intravenous sodium bicarbonate.
  • Secondary amines such as nortriptyline and desipramine are more noradrenergic and better tolerated than tertiary amines such as amitriptyline and imipramine. Clomipramine is the most serotonergic and is used in obsessive compulsive disorder; imipramine is used in childhood enuresis; amitriptyline is used in neuropathic pain and migraine prophylaxis.
  • Monoamine oxidase inhibitors: phenelzine, tranylcypromine and isocarboxazid are non-selective and irreversible; selegiline is selective for MAO-B at low dose and is available as a transdermal patch; moclobemide is a reversible inhibitor of MAO-A. They are particularly useful in atypical depression.
  • Bupropion inhibits noradrenaline and dopamine reuptake. It does not cause sexual dysfunction or weight gain and also aids smoking cessation, but it lowers the seizure threshold, so it is contraindicated in seizure disorders, bulimia and anorexia nervosa.
  • Mirtazapine blocks presynaptic alpha 2 autoreceptors and 5-HT2 and 5-HT3 receptors. It causes marked sedation and appetite gain, which is useful in depressed patients with insomnia and weight loss, and it causes little sexual dysfunction. Rarely it causes agranulocytosis.
  • Trazodone blocks 5-HT2 receptors and is mostly used in low dose as a hypnotic; it can cause priapism, which is a urological emergency.
  • Vortioxetine and vilazodone combine serotonin transporter inhibition with 5-HT1A partial agonism. Esketamine, given intranasally, acts at the NMDA receptor and is used with an oral antidepressant in treatment-resistant depression.

Interactions, Toxicity Syndromes and Monitoring

Three interaction syndromes account for most antidepressant emergencies: serotonin syndrome, the hypertensive tyramine reaction with monoamine oxidase inhibitors, and antidepressant discontinuation syndrome. Recognising them from a vignette is a standard exam task.

  • Serotonin syndrome arises from excess serotonergic activity, most often when two serotonergic agents are combined. The triad is altered mental state (agitation, confusion), autonomic instability (fever, tachycardia, sweating, diarrhoea) and neuromuscular excitability (tremor, hyperreflexia, clonus, especially in the lower limbs). Onset is rapid, within hours.
  • Culprit combinations include an SSRI with a monoamine oxidase inhibitor, tramadol, linezolid, triptans, St John's wort, dextromethorphan, ondansetron or lithium.
  • Management of serotonin syndrome: stop the offending drugs, give supportive care with cooling and benzodiazepines, and use cyproheptadine, a serotonin antagonist, in severe cases.
  • A washout of at least 14 days is required between a monoamine oxidase inhibitor and another antidepressant. After fluoxetine, wait 5 weeks before starting a monoamine oxidase inhibitor because of its long half-life.
  • Tyramine (cheese) reaction: monoamine oxidase inhibitors prevent breakdown of dietary tyramine in aged cheese, cured meats, fermented soy, draught beer and red wine, releasing stored noradrenaline and causing a hypertensive crisis with severe headache. Treat with phentolamine.
  • Serotonin syndrome is easily confused with neuroleptic malignant syndrome. Serotonin syndrome comes on within hours with hyperreflexia and clonus and often diarrhoea; neuroleptic malignant syndrome develops over days with lead-pipe rigidity, bradyreflexia and a raised creatine kinase.
  • Discontinuation syndrome after abrupt withdrawal, most often with paroxetine or venlafaxine: flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances described as electric shocks, and hyperarousal.
  • Antidepressant monotherapy in bipolar disorder can precipitate a switch into mania, so a mood stabiliser must be used alongside or instead.
  • Practical selection: fluoxetine has the most paediatric evidence; sertraline is preferred in cardiac disease and breastfeeding; mirtazapine suits insomnia with poor appetite; bupropion suits sexual dysfunction or smoking cessation; duloxetine or a tricyclic suits comorbid neuropathic pain; paroxetine and tricyclics are avoided in the elderly because of anticholinergic burden and falls.

Key Terms

Monoamine hypothesis
The proposal that depression involves reduced serotonergic and noradrenergic transmission, which all current antidepressants act to increase.
Serotonin syndrome
An acute, potentially fatal excess of serotonergic activity presenting with altered mental state, autonomic instability and neuromuscular hyperexcitability with clonus; treated by withdrawal, supportive care and cyproheptadine.
Tyramine reaction
A hypertensive crisis triggered when a patient on a monoamine oxidase inhibitor eats tyramine-rich food such as aged cheese, releasing stored noradrenaline.
Discontinuation syndrome
Flu-like symptoms, dizziness, insomnia and electric-shock sensations after abrupt cessation of an antidepressant, most common with short half-life drugs such as paroxetine and venlafaxine.

Practice Quiz — 20 Questions

correct out of 20

  1. The mechanism of action of fluoxetine is:

    • A.Blockade of the serotonin transporter
    • B.Inhibition of monoamine oxidase A
    • C.Blockade of dopamine D2 receptors
    • D.Agonism at GABA-A receptors
    A. Blockade of the serotonin transporter — Fluoxetine is a selective serotonin reuptake inhibitor and blocks the serotonin transporter, raising synaptic serotonin.

  2. Why does antidepressant benefit take several weeks despite an immediate rise in synaptic monoamines?

    • A.The drugs accumulate slowly in fat
    • B.Adaptive receptor and neuroplastic changes are required
    • C.Absorption is very slow
    • D.Metabolites are the active drug
    B. Adaptive receptor and neuroplastic changes are required — The delay is attributed to downstream adaptations such as receptor downregulation and increased neurotrophic signalling, not to transmitter levels alone.

  3. Which SSRI has the longest half-life and is therefore least likely to cause discontinuation symptoms?

    • A.Paroxetine
    • B.Sertraline
    • C.Fluoxetine
    • D.Fluvoxamine
    C. Fluoxetine — Fluoxetine and its active metabolite norfluoxetine persist for days, effectively self-tapering.

  4. Which SSRI carries a dose limit because of QT interval prolongation?

    • A.Citalopram
    • B.Sertraline
    • C.Fluoxetine
    • D.Fluvoxamine
    A. Citalopram — Citalopram produces dose-dependent QT prolongation, so maximum doses are capped, particularly in older patients.

  5. The most common persistent adverse effect of SSRIs is:

    • A.Weight loss
    • B.Sexual dysfunction
    • C.Hair loss
    • D.Hyperkalaemia
    B. Sexual dysfunction — Reduced libido, delayed orgasm and erectile difficulty affect a large proportion of patients and rarely resolve with time.

  6. An elderly patient started on sertraline develops confusion and a serum sodium of 124 millimoles per litre. The likely cause is:

    • A.Serotonin syndrome
    • B.Syndrome of inappropriate antidiuretic hormone secretion
    • C.Neuroleptic malignant syndrome
    • D.Lithium toxicity
    B. Syndrome of inappropriate antidiuretic hormone secretion — SSRIs are a recognised cause of drug-induced hyponatraemia through inappropriate antidiuretic hormone release, especially in the elderly.

  7. Which antidepressant class blocks muscarinic, histamine H1 and alpha 1 receptors in addition to monoamine reuptake?

    • A.SSRIs
    • B.Tricyclic antidepressants
    • C.Monoamine oxidase inhibitors
    • D.SNRIs
    B. Tricyclic antidepressants — This off-target receptor blockade explains tricyclic dry mouth, sedation, weight gain and postural hypotension.

  8. A patient who has taken an overdose of amitriptyline has a widened QRS complex. The correct treatment is:

    • A.Intravenous sodium bicarbonate
    • B.Flumazenil
    • C.Naloxone
    • D.Activated charcoal alone
    A. Intravenous sodium bicarbonate — Sodium bicarbonate overcomes the sodium channel blockade responsible for QRS widening and arrhythmia in tricyclic toxicity.

  9. The three Cs of tricyclic overdose are:

    • A.Cough, cyanosis, collapse
    • B.Coma, convulsions, cardiotoxicity
    • C.Confusion, constipation, cramps
    • D.Chills, colic, clonus
    B. Coma, convulsions, cardiotoxicity — Coma, convulsions and cardiotoxicity summarise the life-threatening features of tricyclic poisoning.

  10. Which tricyclic is most serotonergic and is used in obsessive compulsive disorder?

    • A.Desipramine
    • B.Nortriptyline
    • C.Clomipramine
    • D.Doxepin
    C. Clomipramine — Clomipramine has the strongest serotonin reuptake inhibition of the tricyclics and has established efficacy in obsessive compulsive disorder.

  11. A patient taking phenelzine eats aged cheese and develops a severe headache with blood pressure of 220 over 130. The mechanism is:

    • A.Serotonin excess at 5-HT1A receptors
    • B.Failure to metabolise dietary tyramine, releasing stored noradrenaline
    • C.Direct alpha 1 agonism by cheese proteins
    • D.Acute renal failure
    B. Failure to metabolise dietary tyramine, releasing stored noradrenaline — Monoamine oxidase inhibition allows tyramine to reach the circulation and displace noradrenaline from nerve terminals, causing a hypertensive crisis.

  12. Which antidepressant is contraindicated in a patient with bulimia nervosa and a seizure history?

    • A.Mirtazapine
    • B.Bupropion
    • C.Sertraline
    • D.Venlafaxine
    B. Bupropion — Bupropion lowers the seizure threshold, and the risk is compounded by electrolyte disturbance in eating disorders.

  13. A depressed patient with insomnia and marked weight loss would benefit most from:

    • A.Bupropion
    • B.Fluoxetine
    • C.Mirtazapine
    • D.Tranylcypromine
    C. Mirtazapine — Mirtazapine causes sedation and increased appetite through H1 and 5-HT2 blockade, which is therapeutic in this presentation.

  14. Priapism is a recognised adverse effect of:

    • A.Trazodone
    • B.Sertraline
    • C.Nortriptyline
    • D.Moclobemide
    A. Trazodone — Trazodone, through alpha 1 blockade, can cause prolonged painful erection requiring urgent urological care.

  15. Which antidepressant also has a licensed indication for diabetic peripheral neuropathic pain?

    • A.Escitalopram
    • B.Duloxetine
    • C.Mirtazapine
    • D.Phenelzine
    B. Duloxetine — Duloxetine, an SNRI, is approved for diabetic peripheral neuropathy and fibromyalgia in addition to depression.

  16. The minimum washout period after stopping fluoxetine before starting a monoamine oxidase inhibitor is:

    • A.24 hours
    • B.3 days
    • C.2 weeks
    • D.5 weeks
    D. 5 weeks — Because norfluoxetine has a very long half-life, a 5-week washout is required to avoid serotonin syndrome.

  17. Which feature best distinguishes serotonin syndrome from neuroleptic malignant syndrome?

    • A.Fever
    • B.Clonus and hyperreflexia with onset over hours
    • C.Lead-pipe rigidity
    • D.Altered mental state
    B. Clonus and hyperreflexia with onset over hours — Serotonin syndrome develops within hours with neuromuscular hyperexcitability; neuroleptic malignant syndrome evolves over days with rigidity and reduced reflexes.

  18. The first-line treatment for severe serotonin syndrome, after stopping the causative drugs, includes:

    • A.Cyproheptadine and benzodiazepines
    • B.Haloperidol
    • C.Bromocriptine
    • D.Physostigmine
    A. Cyproheptadine and benzodiazepines — Cyproheptadine is a serotonin antagonist and benzodiazepines control agitation and rigidity; antipsychotics are avoided.

  19. Giving an antidepressant alone to a patient with bipolar disorder risks:

    • A.Precipitating a manic switch
    • B.Causing agranulocytosis
    • C.Inducing hypothyroidism
    • D.Causing tardive dyskinesia
    A. Precipitating a manic switch — Antidepressant monotherapy can trigger mania or rapid cycling, so a mood stabiliser is required.

  20. All antidepressants carry a boxed warning regarding:

    • A.Hepatic failure in the elderly
    • B.Increased suicidal ideation in patients under about 25
    • C.Permanent visual loss
    • D.Aplastic anaemia
    B. Increased suicidal ideation in patients under about 25 — Regulators require a warning about increased suicidal thinking and behaviour in children, adolescents and young adults, with close monitoring early in treatment.

References