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Tricyclic and Tetracyclic Antidepressants (TCAs)

Reviewed by: HU Medical Review Board | Last reviewed: September 2023

Tricyclic and tetracyclic antidepressants (TCAs) are drugs used to treat major depressive disorder (MDD). TCAs are older drugs that can have many side effects. Because of this, they are not often the first drugs used to treat depression.1,2

Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are usually the first-line drugs to treat MDD. But each person’s treatment plan will be different.1,2

TCAs are approved by the US Food and Drug Administration (FDA) for depression. But they may be prescribed off-label in treating migraines, fibromyalgia, diabetes-related nerve pain, and more. Off-label use means using a drug for a different purpose than it is officially approved for. One TCA, clomipramine, also is approved for obsessive-compulsive disorder (OCD).2-5

How do TCAs work?

Like many other antidepressant drugs, TCAs impact the balance of neurotransmitters in the body. Neurotransmitters are chemicals that the brain and nerve cells use to send signals. Many of these signals play a role in mood, bodily functions, and more. Two of the main neurotransmitters thought to be involved in depression are serotonin and norepinephrine.6,7

TCAs affect the release and recycling of serotonin and norepinephrine. This is similar to how SSRIs and SNRIs work. But TCAs impact other neurotransmitters, too, like acetylcholine and histamine. TCAs are sometimes called broad-spectrum antidepressants for this reason. Because they act on several neurotransmitters, they have more side effects than newer, more specific drugs.2-5

Examples of TCAs

TCA drugs include:2-4,8

  • Amoxapine (Asendin®)
  • Amitriptyline (Elavil®)
  • Clomipramine (Anafranil®)
  • Desipramine (Norpramin®)
  • Nortriptyline (Pamelor®)
  • Doxepin (Sinequan®)
  • Trimipramine (Surmontil®)
  • Imipramine (Tofranil®)
  • Protriptyline (Vivactil®)
  • Maprotiline (Ludiomil®)

Which TCA your doctor prescribes will depend on a few factors. They will consider your other medical conditions, past treatment history, other drugs you are taking, and more to determine which option is best for you. TCAs are not often prescribed for kids and older adults due to the risk of side effects.1,2

What are the possible side effects?

Side effects can vary based on the specific drug you are taking. Common side effects of TCAs include:2-5,8

  • Sleepiness or drowsiness
  • Constipation
  • Dry mouth
  • Sweating
  • Drop in blood pressure when standing that can lead to dizziness (orthostatic hypotension)
  • Being unable to release all of your urine or not urinating enough (urine retention)
  • Blurry vision
  • Increased appetite
  • Weight gain
  • Shakiness (tremors)
  • Sex-related issues, like trouble having or maintaining an erection, decreased sex drive, or problems reaching orgasm

If your TCA drug makes you sleepy, you may need to take it at night before bed. It may not be safe to do certain tasks that require your full attention (like driving or operating machinery) if you are taking a TCA.3

TCAs, like all antidepressants, have a boxed warning, the strictest warning from the FDA. They have this warning because they may increase the risk of suicidal thoughts and behaviors in people under the age of 25. The risk is highest for those just starting an antidepressant or who have recently changed doses.3,4,8

These are not all the possible side effects of TCAs. Talk to your doctor about what to expect when taking a TCA. You also should call your doctor if you have any changes that concern you when taking 1 of these drugs.

Other things to know

In addition to their common side effects, there are a few serious risks of TCAs. These risks will be reviewed with you by your provider.2-5,9

If you notice any new symptoms you are not used to, seek medical guidance on how to proceed.

Tell your doctor if you are pregnant or planning to become pregnant. TCAs are not often used during pregnancy.2-5

You may be prescribed a specific TCA if there are other benefits to using it. For example, if you have migraines along with MDD, you may be started on amitriptyline over other TCAs. This is because amitriptyline is sometimes used off-label to prevent migraines.2,5

It can take several weeks for an antidepressant drug to take full effect. Effects also vary based on the dose used. You may have months of dose or drug changes before you try a TCA. You may try multiple TCAs over time, too.1,2

Your doctor will monitor you closely throughout treatment. If you are having thoughts of harming yourself or others, call or text the Suicide & Crisis Lifeline at 988 right away, any time of day. Or you can chat with a counselor online.10

Before beginning treatment for depression, tell your doctor about all your health conditions and any other drugs, vitamins, or supplements you are taking. This includes over-the-counter drugs.

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