What drugs are classified as TCA?

October 10, 2025 •

3 min read

Tricyclic antidepressants (TCAs) were one of the first classes of antidepressants, approved in the late 1950s. While newer alternatives are more common today, it is essential for patients and healthcare providers to understand what drugs are classified as TCA and their pharmacological properties. This guide provides a comprehensive overview of these important medications.

Quick Summary

Tricyclic antidepressants, or TCAs, are an older class of medications with a distinctive three-ring chemical structure. This guide outlines which drugs are classified as TCAs, detailing the subclasses of tertiary and secondary amines, how they function, and their current therapeutic applications beyond just depression.

Key Points

Tertiary Amine TCAs: This subclass includes amitriptyline, clomipramine, doxepin, imipramine, and trimipramine, which primarily inhibit serotonin reuptake.
Secondary Amine TCAs: Drugs in this group, such as desipramine, nortriptyline, protriptyline, and amoxapine, are more selective for norepinephrine reuptake.
Diverse Therapeutic Uses: While initially for depression, TCAs are also used for neuropathic pain, migraine prevention, OCD (clomipramine), and insomnia.
Mechanism of Action: TCAs increase neurotransmitter levels (serotonin and norepinephrine) by blocking their reuptake into nerve cells.
Prominent Side Effects: Common adverse effects include dry mouth, constipation, sedation, and cardiac issues, especially with tertiary amines.
Second-Line Treatment: Due to a higher risk of side effects and overdose toxicity, TCAs are typically used as a second-line treatment for depression after safer options.

Understanding Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are a class of medications primarily used to treat major depressive disorder, though they have numerous other applications. Their unique three-ring chemical structure gives them their name. Introduced in the 1950s, TCAs work by increasing levels of neurotransmitters like serotonin and norepinephrine in the brain, which can improve mood. While still effective, they are used less often than newer antidepressants due to more side effects and higher risk in overdose.

How TCAs Work

TCAs prevent the reuptake of norepinephrine and serotonin in the brain, increasing their concentration in the synaptic cleft and boosting their activity. Besides this primary action, TCAs also interact with other receptors, including histamine, acetylcholine, and alpha-1 adrenergic receptors. These interactions contribute to many common side effects like sedation and dry mouth.

What Drugs Are Classified as TCA?

TCAs are divided into two main groups based on their chemical structure: tertiary amines and secondary amines. This difference affects how they work and their side effect profiles.

Tertiary Amines

Tertiary amine TCAs have a tertiary-amine side chain and primarily inhibit serotonin reuptake. They are often more sedating and have more anticholinergic side effects.

Amitriptyline (Elavil®, Vanatrip®): Used for depression, chronic pain, and migraine prevention.
Clomipramine (Anafranil®): Known for treating obsessive-compulsive disorder (OCD).
Doxepin (Silenor®, Sinequan®): Prescribed for depression, anxiety, insomnia, and chronic pain.
Imipramine (Tofranil®): Treats depression and childhood bedwetting.
Trimipramine (Surmontil®): Used for depression and insomnia.

Secondary Amines

Secondary amine TCAs have a secondary-amine side chain and mainly inhibit norepinephrine reuptake. They tend to have fewer side effects than tertiary amines.

Desipramine (Norpramin®): A metabolite of imipramine, it focuses more on norepinephrine.
Nortriptyline (Pamelor®, Aventyl®): A metabolite of amitriptyline, often better tolerated for depression and nerve pain.
Protriptyline (Vivactil®): Has an energizing effect and is used for depression and narcolepsy.
Amoxapine (Asendin®): Also possesses some antipsychotic properties.

Comparison of Tertiary vs. Secondary TCAs


Feature	Tertiary Amines	Secondary Amines
Examples	Amitriptyline, Imipramine, Doxepin	Desipramine, Nortriptyline, Protriptyline
Neurotransmitter Focus	Higher affinity for serotonin (5-HT) reuptake inhibition.	Higher affinity for norepinephrine (NE) reuptake inhibition.
Side Effect Profile	More prominent anticholinergic and sedative effects.	Generally better tolerated with fewer side effects.
Sedation	Often more sedating, may help with insomnia.	Less sedating, sometimes described as energizing.
Weight Gain	Higher likelihood of causing weight gain.	Lower likelihood compared to tertiary amines.

Therapeutic Applications Beyond Depression

TCAs are used for more than just depression:

Neuropathic Pain: Effective for nerve pain conditions like diabetic neuropathy and postherpetic neuralgia, often at lower doses than for depression.
Migraine and Headache Prophylaxis: Amitriptyline and doxepin can help prevent migraines and tension headaches.
Insomnia: Sedating TCAs like doxepin and amitriptyline are used for sleep, particularly at low doses.
Obsessive-Compulsive Disorder (OCD): Clomipramine is an important treatment option for OCD.
Nocturnal Enuresis (Bedwetting): Imipramine is used for childhood bedwetting, though not as a first choice.

Safety Considerations and Side Effects

TCAs can have significant side effects and are risky in overdose. Common side effects are due to their effects on various receptors and include:

Anticholinergic effects: Dry mouth, blurred vision, constipation, urinary retention.
Cardiovascular effects: Risk of abnormal heart rhythms and dizziness from low blood pressure, especially in overdose.
Central Nervous System effects: Sedation, dizziness, confusion.
Weight gain and Sexual dysfunction: Possible with long-term use.
Suicidal Ideation: Like other antidepressants, TCAs carry a warning about increased risk of suicidal thoughts in young adults and adolescents.

Because of these risks, TCAs are often used when newer antidepressants haven't worked. Treatment typically starts low and increases gradually under medical supervision. For detailed drug information, resources like RxList are available.

Conclusion

Tricyclic antidepressants, classified as tertiary or secondary amines, are an older class of medications with uses for depression, chronic pain, and other conditions. While largely superseded by newer, safer drugs, TCAs remain valuable for difficult-to-treat cases and specific disorders. Their use requires careful monitoring due to potential side effects and overdose risk, highlighting their significant role in pharmacology.

Frequently Asked Questions

TCA drugs are primarily classified into two subclasses based on their chemical structure: tertiary amines (e.g., amitriptyline) and secondary amines (e.g., nortriptyline).

Yes, TCAs are still prescribed, though less commonly than newer antidepressants like SSRIs. They are often reserved for cases of severe or treatment-resistant depression and for other conditions such as chronic pain and migraine prevention.

Clomipramine (Anafranil) is the TCA with specific FDA approval for treating obsessive-compulsive disorder (OCD).

TCAs are less selective than SSRIs, meaning they affect more types of receptors in the body, including those for histamine, acetylcholine, and norepinephrine. This broader action results in a wider range of side effects compared to SSRIs.

Tertiary amine TCAs, such as amitriptyline, doxepin, and imipramine, are generally more likely to cause sedation than secondary amines. This is due to their stronger effects on histamine receptors.

TCAs can cause cardiovascular complications, including orthostatic hypotension (low blood pressure when standing) and potentially dangerous heart rhythm problems (arrhythmias), especially in cases of overdose.

Yes, TCAs have a higher risk of toxicity in overdose compared to newer antidepressants. Overdoses can lead to serious complications like severe anticholinergic symptoms, seizures, and cardiac arrest.