What medications are considered TCAs? A comprehensive guide to Tricyclic Antidepressants

October 8, 2025 •

4 min read

First introduced in the late 1950s, tricyclic antidepressants (TCAs) were among the earliest medications used for depression. While newer options are often prescribed first, understanding what medications are considered TCAs is important, as they remain valuable for specific conditions and treatment-resistant cases.

Quick Summary

This guide lists common tricyclic antidepressants (TCAs), details their mechanism, and compares their side effect profile to other medication classes. It also covers their therapeutic uses and important safety considerations.

Key Points

TCA Classification: Tricyclic Antidepressants (TCAs) are categorized into tertiary amines (e.g., amitriptyline) and secondary amines (e.g., nortriptyline), which differ in their side effect profiles.
Mechanism of Action: TCAs work by inhibiting the reuptake of norepinephrine and serotonin, increasing their concentration in the brain, but also affect other receptors.
Primary Examples: Key TCA medications include amitriptyline, imipramine, nortriptyline, desipramine, doxepin, and clomipramine.
Diverse Uses: Beyond depression, TCAs are used off-label for chronic pain, migraine prevention, insomnia, and OCD (specifically clomipramine).
Significant Side Effects: Common side effects include dry mouth, constipation, and drowsiness, while serious risks involve cardiac issues and overdose potential.
Second-Line Therapy: Due to a less favorable side effect profile and higher overdose risk, TCAs are often prescribed after newer antidepressants like SSRIs have been tried.

What are Tricyclic Antidepressants (TCAs)?

Tricyclic antidepressants (TCAs) are a class of medications that get their name from their characteristic three-ringed chemical structure. Developed in the 1950s, they were once a first-line treatment for major depressive disorder but are now often considered a second-line option due to the availability of newer antidepressants with more tolerable side effect profiles, such as selective serotonin reuptake inhibitors (SSRIs).

TCAs exert their effects by inhibiting the reuptake of two key neurotransmitters in the brain: norepinephrine and serotonin. By preventing these chemical messengers from being reabsorbed by nerve cells, TCAs increase their levels in the synaptic cleft, helping to improve mood and attention. However, TCAs are not selective and also affect other chemical messengers, which is responsible for many of their well-known side effects.

Medications Considered TCAs

TCAs can be broadly categorized based on their chemical structure, specifically the type of side chain attached to the three-ring core. This distinction influences their pharmacological profile and side effect characteristics.

Tertiary Amine TCAs

This group of TCAs typically has a higher affinity for serotonin reuptake inhibition and is generally associated with stronger sedative and anticholinergic effects.

Common Tertiary Amine TCAs include:

Amitriptyline (Elavil): An older, well-studied TCA often used for depression, neuropathic pain, and migraine prevention.
Imipramine (Tofranil): The first TCA approved by the FDA, used for depression and bedwetting in children.
Doxepin (Silenor, Sinequan): Prescribed for depression, anxiety, insomnia, and certain chronic pain conditions.
Clomipramine (Anafranil): Known for its strong effect on serotonin, it is primarily used to treat obsessive-compulsive disorder (OCD).
Trimipramine (Surmontil): Occasionally used for depression.

Secondary Amine TCAs

These TCAs are often metabolites of tertiary amines and typically have a more potent effect on norepinephrine reuptake inhibition. They are generally better tolerated with fewer side effects than tertiary amines.

Common Secondary Amine TCAs include:

Nortriptyline (Pamelor): The metabolite of amitriptyline, used for depression and chronic pain management, with a more favorable side effect profile.
Desipramine (Norpramin): The metabolite of imipramine, known for its specific effect on norepinephrine and better tolerance.
Protriptyline (Vivactil): Prescribed for depression.

Common Uses and Indications of TCAs

While originally developed for major depression, TCAs are now more frequently prescribed for other conditions, often on an "off-label" basis.

FDA-approved uses:

Major Depressive Disorder (MDD): Several TCAs are approved for MDD, though they are usually reserved for cases that do not respond to newer antidepressants.
Obsessive-Compulsive Disorder (OCD): Clomipramine is specifically FDA-approved for treating OCD.
Bedwetting (Nocturnal Enuresis): Imipramine is used to treat bedwetting in children.

Common off-label uses:

Chronic Pain: TCAs are effective for various chronic pain conditions, including diabetic neuropathy, fibromyalgia, and migraines.
Insomnia: The sedating properties of certain TCAs, such as doxepin, can be beneficial for treating sleep disorders.
Anxiety Disorders: Some TCAs are used to manage certain types of anxiety.

Comparison of TCAs with SSRIs


Feature	Tricyclic Antidepressants (TCAs)	Selective Serotonin Reuptake Inhibitors (SSRIs)
Mechanism	Inhibit reuptake of both serotonin and norepinephrine.	Selectively inhibit reuptake of serotonin.
Selectivity	Less selective, also blocking other receptors (muscarinic, histamine) leading to more side effects.	Highly selective for serotonin, resulting in fewer side effects.
Side Effect Profile	Higher incidence of side effects like dry mouth, constipation, dizziness, and heart issues.	Generally better tolerated with fewer anticholinergic and cardiovascular side effects.
Overdose Risk	Higher risk of toxicity and fatal overdose due to a narrow therapeutic index.	Generally lower risk of toxicity in overdose.
First-Line Use	Less common due to greater side effect burden, reserved for treatment-resistant cases.	Most commonly prescribed as first-line treatment for depression and anxiety.

Side Effects and Safety Considerations

Due to their lack of selectivity, TCAs are associated with a broader range of side effects than newer antidepressants.

Common side effects:

Dry mouth
Constipation
Dizziness or lightheadedness, especially when standing (orthostatic hypotension)
Drowsiness or fatigue
Weight gain
Blurred vision
Difficulty urinating

Serious side effects and warnings:

Cardiac Issues: TCAs can cause heart rhythm problems (arrhythmias), especially at higher doses or in individuals with pre-existing heart conditions. They are contraindicated after a recent heart attack.
Overdose Risk: The narrow therapeutic index of TCAs means that a relatively small overdose can be life-threatening. Cardiotoxicity is a major concern.
Increased Suicidal Thoughts: All antidepressants carry a boxed warning about an increased risk of suicidal thoughts and behavior, particularly in children, adolescents, and young adults.
Drug Interactions: TCAs should not be taken with monoamine oxidase inhibitors (MAOIs) and can interact with many other medications.
Anticholinergic Effects: These can cause or worsen conditions like angle-closure glaucoma and urinary retention.

Conclusion

While newer medications like SSRIs have largely replaced TCAs as the first-line treatment for depression, tricyclic antidepressants remain an important part of the pharmacology landscape. Their unique mechanism of action makes them highly effective for certain conditions, such as chronic pain and treatment-resistant depression. For some patients, the benefits of a TCA can outweigh the risks, particularly when other treatments have failed. However, careful medical supervision and consideration of their side effect profile and toxicity potential are essential for safe use.

[MedlinePlus provides detailed drug information on imipramine, a representative TCA] (https://medlineplus.gov/druginfo/meds/a682389.html)

Frequently Asked Questions

Tertiary amine TCAs, such as amitriptyline and imipramine, have a stronger effect on serotonin and are typically more sedating with more anticholinergic side effects. Secondary amine TCAs, like nortriptyline and desipramine, primarily affect norepinephrine and are generally better tolerated.

While less commonly used as a first-line treatment for depression compared to SSRIs, TCAs are still prescribed for specific conditions, such as treatment-resistant depression, certain types of chronic pain, and OCD.

Common side effects include dry mouth, constipation, dizziness, drowsiness, blurred vision, and weight gain. The severity and type of side effects can vary depending on the specific TCA.

TCAs have a narrow therapeutic index, meaning the difference between a therapeutic dose and a toxic dose is small. Overdoses can be life-threatening and often involve serious cardiac issues.

Yes, TCAs can affect heart rhythm and are associated with a higher risk of heart problems, especially in individuals with pre-existing heart conditions. They are generally avoided in patients who have recently had a heart attack.

TCAs are generally not considered safe during pregnancy, and alternatives are preferred. Specific TCAs like nortriptyline and desipramine may be considered under careful medical supervision if the benefits outweigh the risks.

TCAs are as effective as SSRIs for treating depression, but they have a higher risk of adverse effects and toxicity. This is why SSRIs are usually the first choice, and TCAs are used when other treatments fail.