Tricyclic antidepressants

Quick revision

Tricyclics work by blocking monoamine reuptake, but nearly everything a student needs to remember about them comes from the receptors they block by accident and from what happens to the heart when too much is taken.

• The amitriptyline label describes inhibition of the membrane pump responsible for uptake of noradrenaline and serotonin in adrenergic and serotonergic neurons. (1)
• Off-target antagonism at muscarinic, histamine H1 and alpha-1 adrenergic receptors generates most of the adverse effects, and none of the antidepressant benefit. (8) (10)
• In poisoning the decisive lesion is cardiac: blockade of fast sodium channels in myocardial cells slows phase 0 of the action potential and widens the QRS complex. (7)
• A QRS prolonged beyond 100 milliseconds is predictive of seizures, and beyond 160 milliseconds is predictive of arrhythmia. (7)
• Every agent in the class carries the antidepressant boxed warning on suicidal thinking and behaviour in children, adolescents and young adults. (1) (2) (3) (4)
• The class divides chemically: amitriptyline, imipramine, doxepin, clomipramine and trimipramine are tertiary amines, while desipramine, nortriptyline and protriptyline are secondary amines. (8)
• Tricyclics are contraindicated during the acute recovery period after a myocardial infarction, and with monoamine oxidase inhibitors inside a fourteen-day window. (2) (4) (3)
• Clomipramine is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder. (4)
• Amitriptyline is used for nerve pain and to help prevent migraines, and the NHS states the doses used for pain are lower than those used for depression. (12)

Overview

Tricyclic antidepressants inhibit the reuptake of serotonin and noradrenaline at presynaptic terminals, raising the concentration of both transmitters in the synaptic cleft. The Pamelor label is unusually frank about the limits of that explanation: the mechanism of mood elevation by tricyclic antidepressants is at present unknown, and what the drug demonstrably does is inhibit the activity of agents as diverse as histamine, 5-hydroxytryptamine and acetylcholine. Reuptake inhibition is the working model, not a proven account of why mood improves. (2) (1) (8)

What displaced these agents from first-line use was not weak efficacy. Tricyclics show equivocal efficacy with SSRIs in major depressive disorder, yet cause more significant adverse effects because of their anticholinergic activity and their lower threshold for overdose. The class also has a narrow therapeutic index. A student who remembers only one thing about tricyclics should remember that the gap between a therapeutic quantity and a dangerous one is small. (8)

The adverse-effect profile is receptor pharmacology made visible. Muscarinic blockade produces dry mouth, blurred vision, constipation and urinary retention, and confusion in older people. Histamine H1 blockade produces sedation, increased appetite and weight gain. Alpha-1 adrenergic blockade induces orthostatic hypotension and dizziness. Each of these is an off-target effect of a molecule that was never selective. (8) (1)

The class has not disappeared. Clomipramine holds a licensed place in obsessive-compulsive disorder, low-dose doxepin is licensed for sleep-maintenance insomnia through H1 antagonism, imipramine remains an option in childhood enuresis, and amitriptyline is widely used for nerve pain and migraine prevention. Reuptake inhibition of noradrenaline and serotonin is believed to underlie the use of tricyclics in neuropathic pain and headache. (4) (6) (3) (12) (8)

Classification and drug examples

Grouped by the amine on the side chain, because that single structural feature tracks the receptor selectivity and, in the case of desipramine, a measurably lighter anticholinergic load. The secondary amines are also the demethylated metabolites of the tertiary amines they sit beside.

Mechanism of action

Reuptake inhibition of noradrenaline and serotonin is the intended action; antagonism at muscarinic, histamine H1 and alpha-1 adrenergic receptors is unintended and accounts for the tolerability problem; and blockade of cardiac fast sodium channels is what makes overdose lethal. The labels do not claim more than the evidence supports, and the nortriptyline label states plainly that the mechanism of mood elevation by tricyclic antidepressants is at present unknown.

Molecular target

Presynaptic noradrenaline and serotonin transporters, with off-target antagonism at muscarinic, histamine H1 and alpha-1 adrenergic receptors, and blockade of cardiac fast sodium channels in overdose

Pharmacodynamic effect

Symptom-modifying rather than curative

Effect kinetics

Effect builds over weeks of continuous exposure rather than with a single dose

1. Inhibition of monoamine reuptake at the presynaptic terminal

   These medicines inhibit serotonin and noradrenaline reuptake within the presynaptic terminals, raising the concentration of both transmitters inside the synaptic cleft. The amitriptyline label puts the same action in older language, describing inhibition of the membrane pump mechanism responsible for uptake of noradrenaline and serotonin in adrenergic and serotonergic neurons. (8) (1)

2. Amine class shifts which transporter dominates

   Tertiary amines typically exhibit significant serotonin reuptake inhibition, whereas secondary amines display heightened inhibition of noradrenaline uptake. Researchers propose that secondary amine agents such as desipramine produce greater noradrenaline blockade than the tertiary amines do. (8) (9)

3. Muscarinic receptor antagonism

   The same molecules act as competitive antagonists at postsynaptic muscarinic receptors. That produces the familiar set of blurred vision, constipation, xerostomia, confusion, urinary retention and tachycardia, and it is the single largest reason the class fell out of first-line use. (8)

4. Histamine H1 antagonism

   Histamine blockade at the H1 receptor may lead to sedation, increased appetite, weight gain and confusion. Doxepin holds the extreme position here, with a binding affinity at H1 quoted as a Ki below 1 nM, and its sleep-maintenance effect is described in its label as possibly mediated through antagonism of that receptor. (8) (6)

5. Alpha-1 adrenergic antagonism

   Alpha-1 adrenergic receptor blockade can induce orthostatic hypotension and dizziness. Imipramine is documented as having strong affinities for alpha-1 adrenergic, histamine H1 and muscarinic M1 receptors, which is why one molecule can cause postural drops, sedation and dry mouth at the same time. (8) (10)

6. Cardiac fast sodium-channel blockade in overdose

   Blockade of fast sodium channels in myocardial cells slows the action potential and provides a membrane stabilising effect. The characteristic QRS prolongation seen in overdose occurs secondary to prolongation of phase 0 of the myocardial action potential, and separate potassium channel blockade lengthens the QT interval and can generate torsades de pointes. (7)

Major clinical uses

Pharmacokinetics

• No dose regimens appear anywhere on this page. Starting, titrating, monitoring or withdrawing a tricyclic is a decision for the treating clinician, working from a current prescribing reference and the individual patient in front of them.
• The metabolite relationships are worth memorising as a pair: amitriptyline yields nortriptyline, and imipramine yields desipramine. In both cases the tertiary amine is demethylated to a secondary amine that is marketed as a drug in its own right. (11) (10)
• CYP2D6 status matters more here than in most classes, because a narrow therapeutic index leaves little room for an unexpectedly high plasma concentration. (10) (8)

Adverse effects

Common

• Antimuscarinic effects: Dry mouth and rarely associated sublingual adenitis, blurred vision, disturbance of accommodation, mydriasis, constipation, paralytic ileus, urinary retention, delayed micturition and dilation of the urinary tract. The clomipramine trials quantify the burden: dry mouth in 84% of patients against 17% on placebo, constipation in 47% against 11%, and abnormal vision in 18% against 4%. (2) (3) (4)
• Sedation, increased appetite and weight gain: Histamine H1 blockade may lead to sedation, increased appetite, weight gain and confusion. Weight gain was reported in 18% of patients receiving clomipramine against 1% on placebo. (8) (4)
• Orthostatic hypotension and dizziness: Alpha-1 adrenergic receptor blockade can induce a postural drop. The imipramine label lists orthostatic hypotension first among its cardiovascular reactions, alongside tachycardia and palpitation, with drowsiness, dizziness, weakness and fatigue listed separately. (8) (3)

Serious adverse effects

• Suicidal thinking and behaviour in the young: The boxed warning states that antidepressants increased the risk compared with placebo of suicidal thinking and behaviour in children, adolescents and young adults in short-term studies of major depressive disorder and other psychiatric disorders. The pooled figures are expressed per thousand treated: 14 additional cases under 18, 5 additional cases from 18 to 24, one fewer case from 25 to 64, and 6 fewer cases at 65 and above. All patients started on an antidepressant for any indication are to be monitored appropriately and observed closely for clinical worsening, suicidality and unusual changes in behaviour. (1) (2) (4)
• Cardiac conduction disturbance and arrhythmia at therapeutic exposure: Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia and prolongation of the conduction time, and myocardial infarction and stroke have been reported with drugs of this class. Desipramine has been linked with heart block, arrhythmias and sudden death. Labels direct extreme caution in cardiovascular disease, with cardiac surveillance at all levels of exposure rather than only at high ones. (1) (3) (9)
• Cardiotoxicity in overdose: Critical manifestations include cardiac dysrhythmias, severe hypotension, shock, congestive heart failure, pulmonary oedema, convulsions and central nervous system depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are the clinically significant indicators of tricyclic toxicity, and the imipramine label calls a maximal limb-lead QRS duration of 0.10 seconds or more the best single indication of severity. Death is most often attributed to hypotension or arrhythmia. This is a medical emergency handled by an emergency service; nothing on this page describes its management. (2) (3) (8)
• Seizures: The clomipramine label reports a cumulative incidence of seizures of 0.64% at 90 days, 1.12% at 180 days and 1.45% at 365 days among exposed patients. In overdose, seizures precede cardiac dysrhythmias and death in some patients, and a QRS beyond 100 milliseconds is predictive of them. A recognised hazard of the class that bears on the choice of agent in anyone with a seizure history. (4) (5) (7)
• Precipitation of angle-closure glaucoma: The pupillary dilation that follows use of many antidepressants including amitriptyline may trigger an angle closure attack in a patient with anatomically narrow angles. Relevant before a tricyclic is chosen for anyone with narrow angles or untreated narrow-angle glaucoma. (1) (6)
• Confusion, delirium and falls in older people: Central anticholinergic effects include cognitive impairment, psychomotor slowing, confusion, sedation and delirium, and geriatric patients are described as particularly sensitive to them. Use of desipramine in the elderly has been associated with a proneness to falling as well as confusional states. This is the effect that most often ends a tricyclic trial in an older patient, and it is a clinician's judgement to make. (1) (5)

Drug-specific effects

• Clomipramine: Sexual dysfunction is prominent: 42% of men experienced ejaculatory failure and 20% impotence, against 2.0% and 2.6% respectively on placebo. (4)
• Nortriptyline: A tendency to produce sinus tachycardia and to prolong the conduction time, so patients with cardiovascular disease are given it only under close supervision. (2)
• Imipramine: Its cardiovascular list runs to heart block, ECG changes, precipitation of congestive heart failure and stroke, which is why cardiac surveillance is specified at every level of exposure. (3)
• Doxepin: Even at the low hypnotic strength, constipation and urinary retention are noted above the licensed maximum, and the product is contraindicated in untreated narrow angle glaucoma or severe urinary retention. (6)
• Desipramine: Overdose may produce cardiac dysrhythmia, severe hypotension, convulsions, coma, hyperactive reflexes, stupor, drowsiness, hypothermia and confusion. (9)
• Amitriptyline: Paralytic ileus and hyperpyrexia sit alongside the ordinary antimuscarinic effects, and hypotension is specifically noted as postural. (1)

Contraindications, precautions and interactions

Contraindications

• Use with a monoamine oxidase inhibitor intended to treat a psychiatric disorder, or within fourteen days of stopping either agent, is contraindicated because of an increased risk of serotonin syndrome. (2) (4) (5)
• The acute recovery period after a myocardial infarction. Every tricyclic label consulted for this page states the same restriction in almost the same words. (2) (4) (3) (1) (5)
• Prior hypersensitivity to the agent or, in the clomipramine label, to other tricyclic antidepressants. (1) (4)
• Low-dose doxepin for insomnia is contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention. (6)

Precautions

• Cardiovascular disease calls for extreme caution, because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes and tachycardia; these patients require cardiac surveillance at all dosage levels. (3)
• Older patients, in whom sensitivity to anticholinergic effects is heightened and falls and confusional states have been reported. (1) (5)
• A history of urinary retention or angle-closure glaucoma, given the anticholinergic properties of these drugs. (1) (5)
• A history of seizures, which matters most for clomipramine given its measured cumulative seizure incidence. (1) (4)
• CYP2D6 poor metaboliser status, since poor metabolisers reach higher than expected tricyclic plasma concentrations and adverse effects become more likely. (10)
• A family history of QT interval prolongation or sudden cardiac death is listed among the reasons to avoid this class. (8)

Drug interactions

• Monoamine oxidase inhibitors: Hyperpyretic crises or severe convulsive seizures may occur in patients receiving such combinations, and the potentiation of adverse effects can be serious or even fatal. A minimum interval of fourteen days is specified when substituting one for the other. (3) (2)
• Other anticholinergic agents: Given together with a tricyclic, close supervision and careful adjustment of dosages are required, because the antimuscarinic burden is additive. (1)
• Sympathomimetics, including adrenaline combined with local anaesthetics: The amitriptyline label singles this combination out as requiring close supervision, which makes it a genuine dental and minor-surgery consideration. (1)
• CYP2D6 inhibitors such as quinidine: Inhibition of CYP2D6 slows tricyclic clearance and drives plasma concentrations up, which is dangerous in a class with a narrow therapeutic index. (5) (8)
• Selective serotonin reuptake inhibitors: Combining a tricyclic with an SSRI is listed among the contraindicated pairings for this class. (8)

Comparison tables

High-yield exam pearls

• Blockade of fast sodium channels in myocardial cells slows the action potential and gives a membrane stabilising effect, and QRS prolongation follows from prolongation of phase 0. (7) It is the mechanistic answer to the most examined question about this class, and it explains why the ECG rather than the plasma level guides severity.
• Two QRS thresholds carry prognostic weight in poisoning: beyond 100 milliseconds predicts seizures, beyond 160 milliseconds predicts arrhythmia. (7) Numbers this specific are examinable, and they show that a single ECG measurement stratifies two different complications.
• Amitriptyline is metabolised to nortriptyline, which is its active form, and imipramine is demethylated by CYP2C19 to desipramine. (11) (10) The parent-metabolite pairs also happen to be the tertiary-to-secondary amine pairs, so one fact answers two different question types.
• Desipramine, compared with tertiary amines such as amitriptyline, is associated with fewer anticholinergic adverse effects. (9) It is the reason a secondary amine is the usual pick when a tricyclic is wanted in an older patient.
• The three off-target receptors map cleanly onto three symptom groups: muscarinic to dry mouth and retention, H1 to sedation and weight gain, alpha-1 to postural dizziness. (8) Examiners test the mapping rather than the list, and the mapping also predicts which patient will not tolerate the drug.
• Clomipramine's cumulative seizure incidence was 0.64% at 90 days, 1.12% at 180 days and 1.45% at 365 days. (4) It is one of very few places where a tricyclic label quantifies a neurological risk over time rather than describing it.

Common exam traps

• Trap: Saying tricyclics were replaced because SSRIs work better. Actually: Efficacy is equivocal with SSRIs in major depressive disorder. What separates them is a heavier anticholinergic burden and a lower threshold for overdose. (8)
• Trap: Attributing overdose deaths mainly to the central nervous system depression. Actually: Death is generally attributed to hypotension or arrhythmia, and the ECG change in QRS axis or width is the clinically significant indicator of toxicity. (8) (2)
• Trap: Treating the antidepressant suicidality boxed warning as an SSRI-only phenomenon. Actually: It appears on tricyclic labels in identical language, covering children, adolescents and young adults in short-term studies of depression and other psychiatric disorders. (1) (3)
• Trap: Assuming any antidepressant may follow a monoamine oxidase inhibitor immediately. Actually: Hyperpyretic crises or severe convulsive seizures may occur, and a minimum of fourteen days must elapse when substituting one class for the other. (3)
• Trap: Thinking a tricyclic is safe soon after a heart attack because the patient is stable. Actually: The acute recovery period following myocardial infarction is a stated contraindication across the class, independent of how well the patient appears. (2) (4)
• Trap: Assuming low-dose doxepin for insomnia carries no tricyclic cautions. Actually: It is still contraindicated in untreated narrow angle glaucoma and in severe urinary retention, and within two weeks of a monoamine oxidase inhibitor. (6)

Self-test questions

Answers are hidden until you open them. These questions are written from this page's cited content and are for study only — they are not clinical guidance.

1. A patient is brought to hospital after a large ingestion of a tricyclic antidepressant. The ECG shows a widened QRS complex. Which mechanism best explains this finding?

   • Blockade of fast sodium channels prolonging phase 0 of the myocardial action potential
   • Antagonism of cardiac muscarinic receptors
   • Blockade of alpha-1 adrenergic receptors in vascular smooth muscle
   • Inhibition of noradrenaline reuptake at cardiac sympathetic nerve endings
   Show answer

   Answer: Blockade of fast sodium channels prolonging phase 0 of the myocardial action potential

   Blockade of fast sodium channels in myocardial cells slows the action potential and provides a membrane stabilising effect, and the characteristic QRS prolongation occurs secondary to prolongation of phase 0 of the myocardial action potential. (7)

2. In tricyclic antidepressant poisoning, which QRS duration is described as predictive of arrhythmia?

   • Greater than 160 milliseconds
   • Greater than 60 milliseconds
   • Greater than 80 milliseconds
   • Greater than 200 milliseconds
   Show answer

   Answer: Greater than 160 milliseconds

   Prolongation of the QRS beyond 100 milliseconds is described as predictive of seizures, while a QRS greater than 160 milliseconds is described as predictive of arrhythmia. (7)

3. Which pairing of parent drug and its active metabolite is correct?

   • Amitriptyline to nortriptyline, and imipramine to desipramine
   • Nortriptyline to amitriptyline, and desipramine to imipramine
   • Clomipramine to nortriptyline, and doxepin to desipramine
   • Imipramine to nortriptyline, and amitriptyline to desipramine
   Show answer

   Answer: Amitriptyline to nortriptyline, and imipramine to desipramine

   Amitriptyline is metabolised to nortriptyline, which is its active form, and imipramine is metabolised by CYP2C19 to desipramine, which is itself a tricyclic antidepressant. (11) (10)

4. Which group do desipramine, nortriptyline and protriptyline belong to, and what does that predict?

   • Secondary amines, with heightened inhibition of noradrenaline uptake
   • Tertiary amines, with heightened inhibition of noradrenaline uptake
   • Secondary amines, with greater serotonin reuptake inhibition
   • Tetracyclic agents, with no effect on monoamine transporters
   Show answer

   Answer: Secondary amines, with heightened inhibition of noradrenaline uptake

   Desipramine, nortriptyline and protriptyline are categorised as secondary amines, and secondary amines display heightened inhibition of noradrenaline uptake, whereas tertiary amines show significant serotonin reuptake inhibition. (8)

5. A tricyclic antidepressant is being considered three days after a monoamine oxidase inhibitor was stopped. What does the labelling require?

   • A minimum interval of fourteen days between the two agents
   • An interval of forty-eight hours is sufficient
   • No interval is required if the doses are low
   • A minimum interval of six months between the two agents
   Show answer

   Answer: A minimum interval of fourteen days between the two agents

   The labels state that concomitant use is contraindicated and that a minimum of fourteen days should elapse when substituting one class for the other, because hyperpyretic crises or severe convulsive seizures may occur. (3) (2)

6. Which cardiac situation is a stated contraindication on tricyclic antidepressant labels?

   • The acute recovery period after a myocardial infarction
   • Well-controlled hypertension
   • A single episode of supraventricular tachycardia ten years ago
   • A resting heart rate at the lower end of normal
   Show answer

   Answer: The acute recovery period after a myocardial infarction

   Tricyclic labels state that the drug is contraindicated during the acute recovery period after a myocardial infarction, and separately warn of conduction defects and arrhythmias in cardiovascular disease. (2) (4) (3)

7. Which receptor effect of the tricyclics best explains sedation, increased appetite and weight gain?

   • Histamine H1 antagonism
   • Muscarinic receptor antagonism
   • Alpha-1 adrenergic antagonism
   • Serotonin transporter blockade
   Show answer

   Answer: Histamine H1 antagonism

   Histamine blockade at H1 may lead to sedation, increased appetite, weight gain and confusion, and doxepin's very high H1 affinity is the basis of its separate licence in sleep-maintenance insomnia. (8) (6)

8. Which tricyclic antidepressant is licensed for the treatment of obsessions and compulsions in obsessive-compulsive disorder?

   • Clomipramine
   • Nortriptyline
   • Protriptyline
   • Trimipramine
   Show answer

   Answer: Clomipramine

   Clomipramine is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder, and the label presumes the effect comes from its action on serotonergic neuronal transmission. (4)

Frequently asked questions

References

1. AMITRIPTYLINE HYDROCHLORIDE tablet, coated — prescribing information DailyMed, U.S. National Library of Medicine
2. PAMELOR (nortriptyline hydrochloride) capsule — prescribing information DailyMed, U.S. National Library of Medicine
3. TOFRANIL (imipramine hydrochloride) tablet, sugar coated — prescribing information DailyMed, U.S. National Library of Medicine
4. ANAFRANIL (clomipramine hydrochloride) capsule — prescribing information DailyMed, U.S. National Library of Medicine
5. NORPRAMIN (desipramine hydrochloride) tablet, sugar coated — prescribing information DailyMed, U.S. National Library of Medicine
6. SILENOR (doxepin hydrochloride) tablet — prescribing information DailyMed, U.S. National Library of Medicine
7. Tricyclic Antidepressant Toxicity — StatPearls StatPearls Publishing, NCBI Bookshelf
8. Tricyclic Antidepressants — StatPearls StatPearls Publishing, NCBI Bookshelf
9. Desipramine — StatPearls StatPearls Publishing, NCBI Bookshelf
10. Imipramine Therapy and CYP2D6 and CYP2C19 Genotype — Medical Genetics Summaries National Center for Biotechnology Information (National Library of Medicine)
11. Nortriptyline — LiverTox: Clinical and Research Information on Drug-Induced Liver Injury National Institute of Diabetes and Digestive and Kidney Diseases, via NCBI Bookshelf
12. About amitriptyline for pain and migraine National Health Service (NHS), United Kingdom

Related drug classes

• SSRI antidepressants
• SNRIs and other antidepressants

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