Tricyclic and Tetracyclic Antidepressants

Medically Reviewed by Jennifer Casarella, MD on August 06, 2020

Tricyclic and tetracyclic antidepressants (TCAs) were some of the first medications to treat depression. Doctors don’t prescribe them 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. Here’s what you need to know.

How Cyclic Antidepressants Work

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 3- or 4-ring chemical structure.

Types of Cyclic Antidepressants

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

Side Effects of Cyclic Antidepressants

Cyclic 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:

Side effects of SSRIs can include:

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

  • Amitriptyline
  • Doxepin
  • Imipramine
  • Trimipramine

People who take these medications seem to handle the side effects of nortriptyline and desipramine better than other TCAs.

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 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.

Other Health Conditions and Cyclic Antidepressants

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

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

Cyclic Antidepressants and Drug Interactions

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.

Treatment With Cyclic Antidepressants

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:

  • Irritability 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 will slowly wean you off the medication.

Show Sources


UpToDate: “Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects.”

Mayo Clinic: “Tricyclic antidepressants and tetracyclic antidepressants,” “Selective serotonin reuptake inhibitors (SSRIs),” “Serotonin Syndrome,” “‘Gut touch?’ Mayo Clinic researchers discover important trigger for serotonin release.”

Depression and Anxiety: “SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability.”

Psychiatric Times: “Not Obsolete: Continuing Roles for TCAs and MAOIs.”

Toxicology International: “Antidepressants Medications and the Relative Risk of Suicide Attempt.” “Can I drink alcohol if I'm taking antidepressants?”

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