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Tricyclic Antidepressants: TCA Side Effects, Uses, And MOA


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Tricyclic antidepressants are among the four common classes of depression medication. TCA medications are some of the oldest depression medicines in existence. They are not as common as they once were, as tricyclic antidepressants (TCAs) have numerous side effects that newer medications do not.

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Learn About TCAs:

What Are Tricyclic Antidepressants?

Tricyclic antidepressants, also called cyclic antidepressants and TCAs for short, are amongst the oldest depression medications in existence. These antidepressant medications are given their classification based on their chemical structure, which features three rings. Tetracyclic depression medications are a type of cyclic depression medication that is closely related to TCAs; however, they have a different number of rings, making them of a separate drug class.

TCAs were developed in the 1950s and have been in use for more than six decades. When they first hit the market, they were considered revolutionary treatment options. However, due to the significant number of side effects they cause and how severe these effects can present, they are no longer considered the first line of treatment. Most people who use cyclic antidepressants do so because newer depression medications have proven not to be effective.

The tricyclic antidepressants list of FDA-approved medications is more extensive than most other depression medication classes. FDA-approved TCA medications are:

  • Amitriptyline
  • Amoxapine
  • Desipramine
  • Doxepin
  • Imipramine
  • Nortriptyline
  • Protriptyline
  • Trimipramine

Because their use has fallen out of favor, even the most common tricyclic antidepressants on the market are not well-known to the general population. In some cases, users who require tricyclic antidepressant drugs may struggle to find a local pharmacy that stocks them.

How Do Tricyclic Antidepressants Work?

What antidepressants do is elevate the mood of the user. How they do this varies between drug classes, and sometimes between drugs within a depression medication category. With TCAs, the mode of action is not entirely clear.

What is known about the tricyclic antidepressant mechanism of action is that it impacts neurotransmitters that ferry communication between brain cells.

Tricyclic antidepressants work by blocks the reuptake of serotonin and norepinephrine. This results in their levels being higher in the brain. As these are “feel-good” chemicals, the end result is an elevated mood.

Like the majority of depression medications on the market, tricyclic antidepressants do not take effect instantly. However, TCA drugs can have a demonstrable impact faster than most other depression medicines. With tricyclic antidepressant drugs, effects can be seen in as little as two weeks, compared to the typical four.

Uses Of Tricyclic Antidepressants

TCA medications have numerous applications. However, they are not first-line medications. This means that when a doctor encounters a condition in a patient that TCA drugs can treat, they try other medications first. If those prove not to be effective, they may then consider tricyclic antidepressants.

By design, TCAs treat depression, including major depressive disorder and mild to moderate depression. Additionally, it is very common to use tricyclic antidepressants for anxiety. In general, their use is only considered once the anxiety has reached debilitating levels.

use of TCAs for pain

Another application is tricyclic antidepressants for pain. This is only an option when the pain is chronic and severe. Types of pain they can treat include:

  • Migraines
  • Tension headaches
  • Diabetic neuropathy
  • Post-herpetic neuralgia

Less-common uses of TCAs include treatment of:

  • Obsessive-compulsive disorder
  • Chronic bedwetting
  • Migraine prevention
  • Panic disorder
  • Bulimia
  • Phantom limb sensations
  • Chronic itching
  • Premenstrual dysphoric disorder
Unlike many other classes, TCAs are not among the antidepressants for weight loss. Also, while they can induce drowsiness, they are not considered ideal antidepressants for sleep disorders.

Tricyclic Antidepressants Contraindications

Tricyclic antidepressants are not suitable for all patients, even those who have tried and not seen success with other drugs. Some of the contraindications for TCAs are as follows:

  • Older adults are more likely to experience severe side effects. In general, use by those over the age of 60 should be avoided.
  • Anyone with a heart condition should not take these drugs as they can cause the pulse to accelerate or become irregular.
  • These medications can cause seizures to occur more frequently in those with such disorders. As a result, they should not be used by anyone who suffers from seizures.
  • Antidepressants and pregnancy are not always safe. Expecting mothers need to discuss the benefits and risks of treatment with their doctors.
  • TCAs can exacerbate certain chronic health issues.

Additionally, tricyclic antidepressant medications can increase the occurrence of suicidal thoughts and tendencies in a patient. The greatest risk is during the first months of treatment, with the danger being heightened in those aged 25 and younger. Patients should be closely monitored until they are stable in their treatment.

confusion from TCAs

Tricyclic Antidepressants Side Effects

There are numerous adverse effects of tricyclic antidepressants. Compared to antidepressant side effects in other classes, they are among the most severe in their expression as well. Some side effects of tricyclic antidepressants are as follows:

  • Disorientation
  • Confusion
  • Racing pulse
  • Irregular pulse
  • Seizures
  • Blurred vision
  • Constipation
  • Dry mouth
  • Drowsiness
  • Low blood pressure upon standing
  • Urine retention
  • Increased appetite
  • Weight gain
  • Excessive sweating
  • Tremors
  • Difficulty achieving and maintaining an erection
  • Delayed orgasm
  • Low sex drive
For many users, the tricyclic antidepressant side effects are too severe to continue treatment. It is important that patients discuss these issues with their doctor to determine if stopping use is best.

Tricyclic Antidepressant Interactions

As with side effects, tricyclic depression medications tend to have more interactions than other depression medications. These interactions are with other drugs, as well as with certain health conditions. All users should research these in-depth before taking drugs.

Interactions With Drugs

Drugs that can interact with TCAs include:

  • MAOIs, as taking them with TCAs can lead to serotonin syndrome, which can be deadly
  • Any drugs that contain phosphate, which is primarily found in bowel preparation medications
  • Tagamet, which can exacerbate the side effects of TCAs
  • Alcohol, as it blocks the depression-fighting effects of TCAs but increases their sedative qualities
  • St. John’s Wort, as it can cause serotonin syndrome
  • Anything containing epinephrine, as this can cause severe high blood pressure
  • Clonidine, which can cause dangerously high blood pressure
Street drugs of all kinds should be avoided while on TCAs. This includes cannabis products regardless of their legality. Even CBD and antidepressants can be problematic. Similarly, alcohol and antidepressants concurrent use should be avoided.

Interactions With Health Conditions

Certain health conditions unrelated to TCA treatment can be made worse by taking these depression medications. Anyone with the following conditions should speak with their doctor to determine if the benefits outweigh the risks or if another form of treatment is needed:

  • Glaucoma
  • Enlarged prostate
  • Diabetes
  • Hear conditions
  • Seizure disorders
  • Liver disease

Additionally, those who already have suicidal tendencies are at risk of feeling them more strongly during the start of treatment. These individuals can likely still take the drugs but will require extra supervision.

stopping TCAs under doctor's supervision

Stopping And Withdrawing From Tricyclic Antidepressants

Depression medications should never be stopped suddenly, including TCAs. While they are not considered addictive, stopping them without tapering can result in the sudden return of depression symptoms that are felt more severely than before treatment. Additionally, going cold turkey can result in withdrawal-like symptoms.

What this process is like will depend on the individual and the medication they were taking. Some potential symptoms one might experience include:

  • Agitation, irritability or anxiety
  • Nausea
  • Sweating
  • Flu-like symptoms
  • Insomnia
  • Lethargy
  • Headache

Users looking into getting off antidepressants should seek out medical supervision for the process. Rehab centers will be able to create a tapering schedule and offer drugs that make the process easier. Once the patient is off the medication for at least two weeks, they will be able to look into alternatives, including over-the-counter antidepressants.

Ending Problematic Tricyclic Antidepressant Use

For anyone who is abusing TCAs or just wants to stop their use due to side effects, seeking out the help of a drug rehab center is best. At these centers, professionals know how to taper the drugs properly and make a plan for addiction treatment, as well as depression. Once treatment is complete, it will be easier to live a healthy life.

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  1. Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Experimental and Clinical Psychopharmacology. 2015;23(1):1–21. doi:10.1037/a0038550.
  2. Amitriptyline. U.S. National Library of Medicine.
Sharon Levy

About Author

Sharon Levy, MD, MPH

After successful graduation from Boston University, MA, Sharon gained a Master’s degree in Public Health. Since then, Sharon devoted herself entirely to the medical niche. Sharon Levy is also a certified addiction recovery coach.


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