Table of Contents
Introduction
Tricyclic antidepressants (TCAs) are one of the oldest classes of antidepressant medications. Although largely replaced by SSRIs due to their improved safety profiles, TCAs are still widely used for treatment-resistant depression, neuropathic pain, and other off-label conditions. They work by inhibiting the reuptake of norepinephrine and serotonin, thereby increasing the levels of these neurotransmitters in the synaptic cleft.
Common TCAs include:
- Amitriptyline
- Nortriptyline
- Imipramine
- Desipramine
- Clomipramine
- Doxepin
These drugs are frequently covered in USMLE, GPAT, NCLEX, and NEET-PG pharmacology sections.
Stepwise Mechanism of Action of TCAs
- Inhibition of reuptake transporters
TCAs inhibit both the norepinephrine transporter (NET) and the serotonin transporter (SERT) on presynaptic neurons. - Increased synaptic levels of NE and 5-HT
This inhibition leads to an accumulation of norepinephrine (NE) and serotonin (5-HT) in the synaptic cleft. - Enhanced postsynaptic neurotransmission
The increased availability of NE and 5-HT leads to improved neurotransmission, which contributes to mood elevation. - Delayed therapeutic response
Like SSRIs, TCAs exhibit a delayed clinical effect, typically seen after 2–4 weeks, due to neuroadaptive changes in receptor sensitivity. - Additional receptor blockade
TCAs also block muscarinic (anticholinergic), histaminergic (H1), and alpha-1 adrenergic receptors, contributing to both therapeutic and adverse effects.

Pharmacokinetic Parameters of TCAs
Drug | Half-life | Metabolism | CYP Interaction | Excretion |
---|---|---|---|---|
Amitriptyline | ~10–28 hours | Hepatic (CYP2D6) | Strong CYP2D6 substrate | Renal |
Nortriptyline | ~18–44 hours | Hepatic | Moderate | Renal |
Imipramine | ~12–25 hours | Hepatic (CYP2D6) | Moderate | Renal |
Desipramine | ~15–24 hours | Hepatic | Moderate | Renal |
Clinical Uses of TCAs
- Major depressive disorder (MDD)
- Neuropathic pain (e.g., diabetic neuropathy)
- Migraine prophylaxis
- Chronic tension-type headaches
- Nocturnal enuresis (imipramine)
- Obsessive-compulsive disorder (clomipramine)
- Insomnia (off-label)
- Fibromyalgia
Adverse Effects of TCAs
- Sedation – due to H1 blockade
- Dry mouth, blurred vision, constipation, urinary retention – anticholinergic effects
- Orthostatic hypotension – alpha-1 blockade
- Weight gain – H1 and 5-HT receptor modulation
- Sexual dysfunction
- Arrhythmias and QT prolongation – sodium channel blockade
- Seizures – especially with overdose
- High lethality in overdose – caution in suicidal patients
Comparative Analysis: TCAs vs SSRIs
Feature | TCAs | SSRIs |
---|---|---|
Reuptake inhibition | NE + 5-HT | Selective for 5-HT |
Receptor blocking | Muscarinic, alpha-1, H1 | Minimal |
Sedation | Common | Less common |
Cardiovascular risk | High (arrhythmias) | Low |
Overdose safety | Dangerous | Safer |
Practice MCQs
Q1. TCAs primarily work by inhibiting:
a. Monoamine oxidase
b. Dopamine reuptake
c. Serotonin and norepinephrine reuptake ✅
d. GABA reuptake
Q2. Which TCA is commonly used in OCD?
a. Amitriptyline
b. Clomipramine ✅
c. Nortriptyline
d. Desipramine
Q3. TCA overdose can lead to:
a. Hepatitis
b. QT prolongation and arrhythmia ✅
c. Parkinsonism
d. Pancreatitis
Q4. Common anticholinergic side effect of TCAs is:
a. Polyuria
b. Diarrhea
c. Dry mouth ✅
d. Tinnitus
Q5. Which receptor blockade causes orthostatic hypotension with TCAs?
a. D2 receptor
b. H1 receptor
c. Muscarinic receptor
d. Alpha-1 adrenergic receptor ✅
Q6. Amitriptyline is useful in:
a. Acute psychosis
b. Migraine prophylaxis ✅
c. Schizophrenia
d. ADHD
Q7. Which TCA is a metabolite of amitriptyline?
a. Imipramine
b. Nortriptyline ✅
c. Clomipramine
d. Desipramine
Q8. Why should TCAs be used cautiously in cardiac patients?
a. Cause bradycardia
b. Cause AV block
c. Block sodium channels and prolong QT ✅
d. Increase renin secretion
Q9. Which symptom is LEAST likely with TCAs?
a. Sedation
b. Constipation
c. Insomnia ✅
d. Blurred vision
Q10. Which CYP enzyme metabolizes many TCAs?
a. CYP3A4
b. CYP2E1
c. CYP2D6 ✅
d. CYP1A2
FAQs
Q1: Are TCAs first-line drugs today?
No. Due to their adverse effect profile and overdose risk, they are usually reserved for treatment-resistant cases.
Q2: Can TCAs cause seizures?
Yes. Especially in high doses or overdose situations.
Q3: Why are TCAs dangerous in overdose?
Because of cardiotoxicity, arrhythmias, and CNS effects. Even a 2-week supply can be lethal.
Q4: Do TCAs cause weight gain?
Yes, especially amitriptyline and doxepin due to histaminergic and serotonergic modulation.
Q5: Can TCAs be used in children?
Not commonly. Imipramine may be used for nocturnal enuresis in select pediatric cases.
References
- KD Tripathi – Essentials of Medical Pharmacology
- Goodman & Gilman – The Pharmacological Basis of Therapeutics
- Review of Pharmacology – Sparsh Gupta
- NCBI: https://www.ncbi.nlm.nih.gov/books/NBK538173/