Tricyclic and Tetracyclic Antidepressants

Medically Reviewed by Zilpah Sheikh, MD on February 22, 2024
Written by Marijke Vroomen Durning, RN, Kristin Mitchell, Nicole Hollimon
7 min read

Tricyclic antidepressants (TCAs) and tetracyclic antidepressants were some of the first medications to treat depression. The difference between tricyclic and tetracyclic antidepressants is in their chemical structure – tricyclics have three rings in their chemical structure, and tetracyclics have four, but they act the same way. Together, they are known as cyclic antidepressants.

Doctors don’t prescribe tricyclic and tetracyclic antidepressants as much as they used to. Other drugs have replaced them, mainly selective serotonin reuptake inhibitors (SSRIs). But they may be an option if you’ve tried more than one of the newer antidepressants and they don’t work for you.

Tricyclic antidepressants vs. SSRIs

Tricyclic antidepressants, tetracyclic antidepressants, and SSRIs are used to treat depression. Tricyclic antidepressants have been around since the 1950s. SSRIs were introduced to the market in the 1980s. 

The drugs work differently in the brain. Tricyclics and tetracyclics affect the norepinephrine and serotonin levels in your brain, while SSRIs only affect serotonin. This means that TCAs can cause more side effects than SSRIs. Tricyclic antidepressants are also more dangerous if you overdose with them.

Cyclic antidepressants boost the levels of serotonin and epinephrine in the brain. These are neurotransmitters that affect your mood. These drugs are called “cyclic” because of their three- or four-ring chemical structure.

There are 10 TCAs approved to treat depression. They are:

Tricyclic antidepressants tend to cause more problems because they affect other neurotransmitters, not just serotonin and epinephrine. One review of several studies found more patients stopped taking TCAs than SSRIs because of the side effects. They can include:

In general, these TCAs are more likely to make you sleepy or lead to weight gain:

  • Amitriptyline
  • Doxepin
  • Imipramine
  • Trimipramine

Two TCAs, nortriptyline and desipramine, appear to have fewer side effects than others in this group.

The main reason doctors switched to SSRIs and other antidepressants is because of the risks of overdose and suicide with TCAs. One study found these risks were much lower in patients taking SSRIs. Your doctor may not prescribe TCAs if you are at risk for taking your own life. If they do, they’ll likely give you very small amounts – about a 1-week supply. Or they may have someone close to you keep the medicine and give it to you as you need it.

Cyclic antidepressants may cause problems if you have certain health conditions. Talk to you doctor if you have:

Ask your doctor if TCAs are OK if you’re pregnant.

Always talk to your doctor about any supplements or medications you take before you start your prescription. Cyclic antidepressants can interact with many common medications. Drinking alcohol while you take them could make you drowsy and affect your coordination.

Your body needs serotonin to regulate your mood, as well as functions like appetite, digestion, and sleep. But if you have too much of it in your system, you can have serious side effects. This is called serotonin syndrome. It’s rare, but it can happen if you:

  • Increase your antidepressant dosage
  • Combine antidepressants
  • Take certain medications, including ones for nausea and migraines
  • Take illegal drugs, such as LSD or cocaine
  • Add supplements to your diet that boost serotonin, such as St. John’s wort

Symptoms include:

These symptoms will show up within hours after you take a higher dose of your medication or combine them with a supplement that raises serotonin. They usually go away once your levels get back to normal, but if you don’t treat them, you can pass out and, in rare cases, die.

Your doctor will likely start you with a low-dose TCA to see how it affects you. You may have to try a few before you find one that works. It can take several weeks to know if it’s helping or for side effects to let up.

Talk to your doctor if you want to stop your medication. Stopping suddenly can cause side effects. They include:

  • Crankiness or anxiety
  • Nausea
  • Sweating
  • Flu-like symptoms, such as chills and muscle aches
  • Trouble sleeping
  • Low energy
  • Headache

To help you stop your TCA safely, your doctor may slowly wean you off the medication.

After you start feeling better or if you’re having side effects from the TCA that are bothering you, you might be tempted to stop taking the medication. This is not a good idea because TCAs can cause withdrawal symptoms if they are stopped too suddenly. The effects can last a few days to a couple of weeks, and even longer for some people. This isn’t because these drugs are addictive – they’re not. But your body is used to the chemical reactions and needs time to adapt to you not taking the medication any longer. You should only stop your treatment with your doctor’s supervision and a plan on how to decrease the dose safely.

Since withdrawal symptoms can also occur if you miss several doses in a row, it’s important to take your medication regularly. If you are having trouble remembering to take your medication, speak with your doctor to see if there are alternatives.

These are some of the most common withdrawal symptoms:.

  • Anxiety
  • Agitation, crankiness
  • Nausea
  • Sweating
  • Chills and muscle aches, as if you might have the flu
  • Insomnia
  • Lethargy
  • Headache

One reason that doctors are prescribing fewer TCAs is because of the overdose risk related to these medications. They have a lower threshold for overdose, which means you don’t have to take too many to take too much. Overdose symptoms usually show within 30 to 40 minutes of the overdose.

Some symptoms of a tricyclic antidepressant overdose include:

  • Heart irregularities
  • Low blood pressure (hypotension)
  • Dry mouth (xerostomia)
  • Urinary retention (not being able to empty your bladder of urine)
  • Slowed breathing
  • Tremors
  • Seizures
  • Coma

If someone has overdosed on a TCA, call 911. It is a medical emergency. Stay on the phone with the 911 operator while you are waiting for help. It is vital that you ensure the person is still breathing and has an open airway. If you’re not sure how to do that, the operator will explain what steps to take.

In the emergency department, doctors will ensure the airway is open and clear and, if necessary, intubate (put a tube down the trachea). Other things they may do if necessary:

  • Give activated charcoal. If the person is not conscious or unable to swallow, the charcoal will be given through a stomach tube inserted through the nose or mouth.
  • Give medications to regulate the heart rhythm.
  • Give medications to stop seizures.
  • Give intravenous (IV) fluids to raise blood pressure.

Here are some situations when you should reach out to your doctor:

  • If you are having side effects that are bothering you
  • If you are not feeling any better or your symptoms are getting worse
  • If you believe you should stop taking the medication

If you have any thoughts of suicide or self-harm, or if you have overdosed, do not wait to speak with your doctor. Go directly to the closest emergency department or call 911. Be sure to tell the emergency personnel the name of the drug you are taking.

Tricyclic antidepressants are not prescribed as often as they used to be, but for some people, they are the right choice. If you have any side effects, don’t stop taking the drug without speaking with your doctor because there may be alternatives or different doses that won’t affect you as much. And if you are feeling any thoughts of suicide or if you overdose, get emergency help right away.

What do TCAs do?

TCAs were developed to treat depression, but they can be prescribed “off label” as well to treat chronic conditions such as:

  • Migraines
  • Insomnia
  • Anxiety
  • Chronic pain
  • Fibromyalgia
  • Bedwetting

What is the most common tricyclic antidepressants?

There are several types of tricyclic antidepressants available in the United States. They include:

  • Amitriptyline (Elavil, Vanatrip)
  • Amoxapine (Asendin)
  • Desipramine (Norpramin)
  • Doxepin (Silenor®, Sinequan)
  • Imipramine (Tofranil, Tofranil-PM)
  • Nortriptyline (Aventyl, Pamelor)
  • Protriptyline (Vivactil)
  • Trimipramine (Surmontil)

How do tetracyclic antidepressants work?

Tetracyclic antidepressants work much like tricyclic antidepressants do. They alter the norepinephrine and serotonin levels in your brain.