Mechanism of Action of Citalopram

Introduction

Citalopram is a selective serotonin reuptake inhibitor (SSRI) widely prescribed for the treatment of major depressive disorder and other mood-related conditions. It is valued for its high selectivity toward the serotonin transporter (SERT), resulting in effective antidepressant action with relatively fewer off-target effects compared to older antidepressants. Citalopram and its S-enantiomer (escitalopram) are frequently tested in pharmacology, psychiatry, and clinical entrance examinations due to their clear mechanism and safety considerations.

Mechanism of Action (Step-wise)

Citalopram exerts its antidepressant effect by selectively inhibiting serotonin reuptake in the central nervous system.

Step-wise mechanism:

1. Serotonin Release
   Serotonin (5-hydroxytryptamine, 5-HT) is released from presynaptic neurons into the synaptic cleft in serotonergic pathways of the brain.
2. Normal Reuptake via SERT
   Under physiological conditions, serotonin is taken back into the presynaptic neuron by the serotonin transporter (SERT), terminating its synaptic action.
3. Selective SERT Inhibition
   Citalopram selectively and competitively inhibits SERT on presynaptic neurons.
4. Increased Synaptic Serotonin
   Inhibition of reuptake leads to increased serotonin concentration in the synaptic cleft.
5. Enhanced Postsynaptic Receptor Activation
   Elevated serotonin levels result in prolonged stimulation of postsynaptic 5-HT receptors.
6. Neuroadaptive Changes
   Chronic SSRI use leads to downregulation of presynaptic autoreceptors (5-HT₁A), enhancing serotonergic neurotransmission and improving mood over time.

Pharmacokinetics

• Absorption: Well absorbed orally
• Bioavailability: Approximately 80%
• Distribution: Widely distributed; crosses the blood–brain barrier
• Metabolism: Hepatic metabolism mainly via CYP2C19, CYP3A4, and CYP2D6
• Elimination: Renal and fecal excretion
• Half-life: Approximately 35 hours
• Steady state: Achieved in 1–2 weeks

Dose adjustment may be required in hepatic impairment and elderly patients.

Clinical Uses

Citalopram is indicated for several psychiatric conditions:

• Major depressive disorder
• Generalized anxiety disorder
• Panic disorder
• Obsessive–compulsive disorder (off-label)
• Social anxiety disorder (off-label)

Its favorable tolerability profile makes it a commonly prescribed first-line antidepressant.

Adverse Effects

Common and important adverse effects include:

• Central nervous system:
  • Insomnia
  • Somnolence
  • Headache
• Gastrointestinal:
  • Nausea
  • Dry mouth
  • Diarrhea
• Sexual dysfunction:
  • Decreased libido
  • Delayed ejaculation
  • Anorgasmia
• Cardiac:
  • QT interval prolongation (dose-dependent, clinically significant)
• Others:
  • Serotonin syndrome (when combined with other serotonergic agents)

Comparative Analysis (must include a table + explanation)

Comparison of Antidepressant Classes

Explanation:
Citalopram offers effective antidepressant action with fewer autonomic and sedative effects compared to tricyclic antidepressants. Unlike MAO inhibitors, it does not require dietary restrictions, improving safety and adherence. However, its risk of QT prolongation limits high-dose use.

MCQs

1. Citalopram primarily inhibits which transporter?
   a) Dopamine transporter
   b) Norepinephrine transporter
   c) Serotonin transporter
   d) GABA transporter

Answer: c) Serotonin transporter

2. Citalopram belongs to which drug class?
   a) SNRI
   b) SSRI
   c) TCA
   d) MAOI

Answer: b) SSRI

3. Increased synaptic serotonin occurs due to:
   a) Increased synthesis
   b) Reduced metabolism
   c) Reuptake inhibition
   d) Vesicular storage

Answer: c) Reuptake inhibition

4. The antidepressant effect of citalopram is delayed because of:
   a) Slow absorption
   b) Autoreceptor downregulation
   c) Poor bioavailability
   d) Rapid clearance

Answer: b) Autoreceptor downregulation

5. Which adverse effect is dose-limiting for citalopram?
   a) Hepatotoxicity
   b) QT prolongation
   c) Nephrotoxicity
   d) Agranulocytosis

Answer: b) QT prolongation

6. Citalopram has minimal effect on which receptor system?
   a) Muscarinic
   b) Histaminic
   c) Alpha-1
   d) All of the above

Answer: d) All of the above

7. Which enzyme is most involved in citalopram metabolism?
   a) CYP1A2
   b) CYP2C19
   c) CYP2E1
   d) CYP4A

Answer: b) CYP2C19

8. Sexual dysfunction with citalopram is due to:
   a) Dopamine blockade
   b) Excess serotonin
   c) Reduced GABA
   d) Increased norepinephrine

Answer: b) Excess serotonin

9. Serotonin syndrome is caused by:
   a) Overdose of SSRIs alone
   b) SSRI and MAOI combination
   c) SSRI withdrawal
   d) SSRI with antipsychotics

Answer: b) SSRI and MAOI combination

10. Which antidepressant is more selective than citalopram?
    a) Fluoxetine
    b) Paroxetine
    c) Escitalopram
    d) Sertraline

Answer: c) Escitalopram

FAQs

1. What is the primary mechanism of citalopram?
   Selective inhibition of serotonin reuptake via SERT.
2. Why does citalopram take weeks to show effect?
   Due to neuroadaptive changes and downregulation of presynaptic autoreceptors.
3. Does citalopram affect norepinephrine or dopamine?
   No, it is highly selective for serotonin.
4. Why is QT prolongation a concern with citalopram?
   It increases the risk of arrhythmias at higher doses.
5. Is citalopram safe in elderly patients?
   Yes, but lower doses are recommended due to QT risk.
6. Can citalopram cause serotonin syndrome?
   Yes, especially when combined with other serotonergic drugs.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  https://accessmedicine.mhmedical.com
• Katzung BG. Basic and Clinical Pharmacology
  https://accessmedicine.mhmedical.com
• Tripathi KD. Essentials of Medical Pharmacology
  https://www.jaypeebrothers.com
• Harrison’s Principles of Internal Medicine
  https://accessmedicine.mhmedical.com

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