Tricyclic antidepressants

Definition and Overview

Tricyclic antidepressants (TCAs) are a class of psychotropic medications that primarily function as antidepressants. They derive their name from their three-ring chemical structure, and were first developed in the 1950s as some of the earliest pharmacologic treatments for depression. TCAs are now used less frequently as first-line antidepressants due to the emergence of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and other newer agents, but they remain clinically relevant in various psychiatric and non-psychiatric indications.

The core pharmacologic mechanism involves inhibiting the reuptake of norepinephrine (NE) and serotonin (5-HT) at presynaptic terminals, increasing their synaptic availability. However, TCAs also act on other receptors—including histamine, muscarinic, and α1-adrenergic—which contribute to their adverse effect profile.

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Mechanism of Action

The primary pharmacodynamic action of TCAs involves:

1. Reuptake Inhibition

   • Serotonin Transporter (SERT): Inhibits serotonin reuptake → ↑ synaptic 5-HT

   • Norepinephrine Transporter (NET): Inhibits norepinephrine reuptake → ↑ synaptic NE

2. Secondary Receptor Blockade

   • Histamine H1 receptor → Sedation, weight gain

   • Muscarinic M1 receptor → Anticholinergic effects (dry mouth, constipation)

   • α1-Adrenergic receptor → Orthostatic hypotension, dizziness

   • Voltage-gated Na⁺ channels (in high doses) → Cardiotoxicity

This broad receptor activity is both a strength (for certain pain and insomnia indications) and a limitation (due to toxicity).

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Common Generic Names in the TCA Class

TCAs are generally divided into tertiary amines (more serotonergic and sedating) and secondary amines (more noradrenergic and stimulating):

Tertiary Amines	Secondary Amines
Amitriptyline	Nortriptyline
Imipramine	Desipramine
Clomipramine	Protriptyline
Doxepin	Amoxapine
Trimipramine	Maprotiline* (technically a tetracyclic)

*Note: Maprotiline is classified under tetracyclic antidepressants but shares similar pharmacologic properties.

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Formulations and Available Routes

• Oral Tablets/Capsules: All TCAs

• Injectable (IV/IM): Limited to imipramine (rare use in emergencies)

• Liquid Oral Solutions: Some available for amitriptyline, nortriptyline (pediatric use or geriatrics)

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FDA-Approved and Off-Label Clinical Uses

Indication	Common TCAs Used	Status
Major Depressive Disorder (MDD)	Amitriptyline, Imipramine, Nortriptyline	Approved
Neuropathic Pain	Amitriptyline, Nortriptyline	Off-label
Migraine Prophylaxis	Amitriptyline	Off-label
Nocturnal Enuresis (bedwetting)	Imipramine	Approved
Insomnia	Doxepin (low dose: 3–6 mg)	Approved (Silenor)
Obsessive-Compulsive Disorder (OCD)	Clomipramine	Approved
Panic Disorder	Imipramine, Clomipramine	Off-label
Fibromyalgia	Amitriptyline	Off-label
ADHD (in children)	Desipramine	Off-label
Irritable Bowel Syndrome (IBS)	Amitriptyline (low dose)	Off-label
Post-Herpetic Neuralgia	Nortriptyline, Desipramine	Off-label

Pharmacokinetics

Drug	Half-Life (hours)	Metabolized by	Active Metabolite
Amitriptyline	10–28	CYP2D6, CYP2C19	Nortriptyline
Nortriptyline	18–44	CYP2D6	None (active parent)
Imipramine	9–25	CYP2D6	Desipramine
Desipramine	12–30	CYP2D6	None
Clomipramine	20–50	CYP2C19, CYP2D6	Desmethylclomipramine
Doxepin	8–24	CYP2D6	Nordoxepin
Trimipramine	12–24	CYP450 enzymes	Active metabolites

Dosing Guidelines (Typical Adult Range)

Drug	Starting Dose (mg/day)	Target Dose (mg/day)	Notes
Amitriptyline	25–50	75–150	Often given at night due to sedation
Nortriptyline	25	75–150	Therapeutic plasma levels (50–150 ng/mL)
Imipramine	25–50	100–200	Used in depression and enuresis
Desipramine	25–50	100–200	Less sedating; higher activation
Clomipramine	25	100–250	Effective for OCD
Doxepin	10	75–300 (low dose: 3–6 mg)	3–6 mg FDA-approved for insomnia (Silenor)

Adverse Effects

TCAs have a high burden of dose-dependent side effects, mainly due to their non-selective receptor activity.

Anticholinergic Effects

• Dry mouth

• Constipation

• Urinary retention

• Blurred vision

• Cognitive impairment (especially in elderly)

CNS Effects

• Sedation (especially with tertiary amines)

• Confusion

• Seizure threshold reduction (especially with clomipramine)

Cardiovascular Effects

• Orthostatic hypotension (α1 blockade)

• Sinus tachycardia

• QT prolongation

• Arrhythmias (especially in overdose)

Weight Gain and Sexual Dysfunction

• H1 antagonism → increased appetite

• Sexual side effects vary by agent

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Toxicity and Overdose Risks

TCAs are lethal in overdose, even with doses 10 times the therapeutic range. This is due to:

• Cardiac sodium channel blockade → QRS prolongation, ventricular arrhythmias

• CNS toxicity → seizures, coma

• Anticholinergic delirium → agitation, hallucinations

Treatment of overdose includes:

• Sodium bicarbonate (cardiac membrane stabilization)

• Activated charcoal (if early presentation)

• Seizure management with benzodiazepines

• Supportive care and ECG monitoring

TCAs are contraindicated in patients with:

• Recent myocardial infarction

• Cardiac conduction defects

• History of seizures (relative)

• Narrow-angle glaucoma

• Urinary retention or prostatic hypertrophy (especially in elderly)

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Drug Interactions

Interacting Agent/Class	Effect / Risk
MAOIs	Hypertensive crisis, serotonin syndrome
SSRIs/SNRIs	↑ Serotonin → serotonin syndrome
Anticholinergic drugs (e.g., benztropine)	↑ Anticholinergic burden → delirium
Alcohol, benzodiazepines	↑ CNS depression
Antiarrhythmics (Class IA, III)	↑ Risk of QT prolongation
CYP2D6 inhibitors (e.g., fluoxetine)	↑ TCA plasma levels → toxicity
Clonidine	Blunted antihypertensive response

Laboratory Monitoring

• Plasma TCA levels are sometimes monitored for nortriptyline, imipramine, and desipramine

• ECG monitoring is recommended in elderly or at high dose

• Serum sodium: TCAs may rarely induce SIADH → hyponatremia

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Comparison with Other Antidepressants

Feature	TCAs	SSRIs	SNRIs
Onset of action	2–4 weeks	1–3 weeks	1–2 weeks
Anticholinergic effects	Prominent	Minimal	Moderate (with venlafaxine)
Weight gain	Common	Variable	Moderate
Overdose toxicity	High	Low	Low
Sedation	Significant (tertiary amines)	Mild to moderate	Mild

Examples of Commercial Brand Names

Generic Name	Brand Names
Amitriptyline	Elavil, Endep, Tryptanol
Nortriptyline	Pamelor, Aventyl
Imipramine	Tofranil
Desipramine	Norpramin
Clomipramine	Anafranil
Doxepin	Sinequan (depression), Silenor (insomnia)
Trimipramine	Surmontil

Clinical Guidelines and Recommendations

• Not first-line for depression unless patient fails SSRIs/SNRIs

• Useful for comorbid pain conditions, insomnia, and treatment-resistant depression

• Start low and go slow, especially in the elderly

• Suicide risk must be assessed before prescribing due to overdose lethality