Tricyclic Antidepressants

2 min read · 7 sections

Tricyclic antidepressants are used to treat depression as well as manage a variety of other conditions, ranging from obsessive-compulsive disorder to bedwetting. They were one of the first types of antidepressants developed, and though they are effective, they have been largely replaced with newer antidepressants due to their potential for varied negative side effects.

However, they may still be used for depression when a person doesn’t respond well to other forms of treatment, and they can be used to treat other conditions such as anxiety, fibromyalgia, chronic pain, and migraines.

What Are Tricyclic Antidepressants?

Tricyclic antidepressants, or TCAs, were first used to manage major depression. They are believed to block the reuptake of the monoamine neurotransmitters—including serotonin and norepinephrine. The resulting increase in activity of these neurotransmitters in the brain is associated with an improvement in certain symptoms of depression. 1,2

Uses of Tricyclic Antidepressants

The primary use of TCAs is for the treatment of major depressive disorder. According to the Diagnostic and Statistical Manual of Mental Disorders, a diagnosis of major depressive disorder is made based on the presence of a range of symptoms, including:3

  • Depressed mood.
  • A loss of interest in once-pleasurable activities.
  • Significant weight gain or loss.
  • Insomnia or sleeping more than usual.
  • Slower movement and functioning that is observed by others.
  • A sense of worthlessness.
  • Inability to concentrate.
  • Loss of energy.
  • Suicidal thoughts or plans.

To meet diagnostic criteria, five or more symptoms must be present over the same 2-week period, and at least one of the symptoms must be depressed mood or loss of pleasure.3

In addition to major depression, TCAs are sometimes used to treat:2,4

  • Anxiety.
  • Obsessive-compulsive disorder (OCD).

Off-label uses include:

  • Panic disorder.
  • Pediatric enuresis.
  • Pruritis.
  • Smoking cessation.
  • Migraine prophylaxis.
  • Chronic pain.
  • Pain in conjunction with: fibromyalgia, diabetes, shingles, phantom limb syndrome.

Since the introduction of other antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), the use of TCAs has declined dramatically. Tricyclics have more negative side effects than these drugs, and they are more dangerous if the person overdoses. In some cases, however, they have proved to be effective in treating depression where other treatments have failed.2

Today, however, TCAs serve as a primary method of treatment for people with neuropathic pain. Used for this purpose, TCAs can be divided into what are called secondary and tertiary amine agents. The secondary amines (nortriptyline, desipramine, and maprotiline) are selective inhibitors of norepinephrine. The tertiary amines (amitriptyline, imipramine, and clomipramine) block the reuptake of both serotonin and norepinephrine, and are relatively more effective for treating neuropathic pain. Studies have shown these drugs to be effective treatments for painful diabetic neuropathy, though it may take several weeks before the patient feels relief from pain.5

Side Effects

As mentioned above, tricyclic antidepressants are used far less often since the introduction of SSRIs and SNRIs, primarily due to their wide range of unpleasant side effects.

The risk of dangerous side effects increases if tricyclics are mixed with alcohol, cimetidine (Tagamet), St. John’s wort, or monoamine oxidase inhibitors (MAOIs).4

Risks & Signs of Overdose

Tricyclic antidepressants may increase the risk of cardiovascular issues. A study in England found that tricyclics were associated with a 35% increased risk of heart disease. The study authors did not find an increased risk with newer antidepressants such as SSRIs.4

It is also possible to overdose on tricyclic antidepressants. Symptoms of an overdose include:6

  • Dilated pupils.
  • Vomiting.
  • Low body temperature.
  • Severely low blood pressure.
  • Shock.
  • Cardiac dysrhythmias.
  • Congestive heart failure.
  • Fluid buildup in the lungs.
  • Restlessness.
  • Confusion.
  • Hallucinations.
  • Convulsions.
  • Stupor.
  • Coma.

An overdose requires immediate medical attention. If you observe the signs of overdose in yourself or someone else, call 911 right away.

People who wish to stop taking tricyclics should speak to their doctor first. Quitting the medications suddenly can lead to withdrawal symptoms such as upset stomach, flu-like symptoms, anxiety, dizziness, “electric shock” sensations, and seizures.7

Combining Talk Therapy with TCAs

Generally, treatment that includes both an antidepressant medication and talk therapy tends to produce better results than either approach on its own. Both approaches can provide relief from symptoms of depression, but better results have been seen when both medications and psychotherapy are combined.

According to researchers, the results of a meta-analysis published in World Psychiatry provide “clear evidence that combined treatment with psychotherapy and antidepressant medication is more effective than treatment with antidepressant medication alone.”8

The National Alliance on Mental Illness makes a similar recommendation, saying that for many, psychotherapy and medications give better results than either treatment alone. They suggest several approaches to therapy that are well-suited to treating depression in combination with medication, including the following:9

  • Cognitive behavioral therapy (CBT): CBT is designed to identify and adjust negative patterns of thought associated with depression by teaching coping strategies to deal with these thoughts.
  • Interpersonal therapy (IPT): This approach focuses on life challenges that may lead to or exacerbate depression, such as relationships. Practitioners work with clients to examine their interactions and teach techniques for improving their relationships with others.
  • Psychodynamic therapy: The goal of this therapy is to recognize unwelcome patterns of feeling and behavior arising from past experiences and to learn techniques for resolving them.

The Importance of Treatment

Despite the presence of newer medications—and new approaches to psychotherapy—first-wave medications such as tricyclic antidepressants can be effective in addressing the challenges faced by those with major depressive disorder or other mental health issues.

Although they can have significant side effects, tricyclic antidepressants may be able to relieve depression and other conditions, such as diabetic neuropathy, in cases where other medications have not. A discussion with your team of medical professionals is the best way to determine if tricyclic antidepressants are the best choice for you.


[1]. American Psychological Association. Tricyclic Antidepressant (TCA).

[2]. National Health Service. (2018). Antidepressants: Overview

[3]. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

[4]. Foley, C. (2018). Tricyclic Antidepressants: Do They Work? University Health News Daily.

[5]. ScienceDirect. Tricyclic Antidepressant.

[6]. Food and Drug Administration. (2007). Pamelor.

[7]. National Health Service. (2018). Antidepressants: Dosage.

[8]. Cuijpers, P. et al. (2014). Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta-analysis. World Psychiatry, 13(1), 56-67.

[9]. National Alliance on Mental Illness. (2017). Depression.

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