Tricyclic antidepressants and tetracyclic antidepressants

Tricyclic and tetracyclic antidepressants affect brain chemicals to ease depression symptoms. Explore their possible side effects and whether one of these antidepressants may be a good option for you.

By Mayo Clinic Staff

Tricyclic and tetracyclic antidepressants, also called cyclic antidepressants, are among the earliest antidepressants developed. They're effective, but they've generally been replaced by antidepressants that cause fewer side effects. However, cyclic antidepressants may be a good option for some people. In certain cases, they relieve depression when other treatments have failed.

Cyclic antidepressants are designated as tricyclic or tetracyclic, depending on the number of rings in their chemical structure — three (tri) or four (tetra).

How cyclic antidepressants work

Cyclic antidepressants ease depression by affecting chemical messengers (neurotransmitters) used to communicate between brain cells. Like most antidepressants, cyclic antidepressants work by ultimately effecting changes in brain chemistry and communication in brain nerve cell circuitry known to regulate mood, to help relieve depression.

Cyclic antidepressants block the reabsorption (reuptake) of the neurotransmitters serotonin (ser-o-TOE-nin) and norepinephrine (nor-ep-ih-NEF-rin), increasing the levels of these two neurotransmitters in the brain. Cyclic antidepressants also affect other chemical messengers, which can lead to a number of side effects.

Cyclic antidepressants approved to treat depression

The Food and Drug Administration (FDA) approved these tricyclic antidepressants to treat depression:

  • Amitriptyline
  • Amoxapine
  • Desipramine (Norpramin)
  • Doxepin
  • Imipramine (Tofranil)
  • Nortriptyline (Pamelor)
  • Protriptyline
  • Trimipramine

The FDA approved the tetracyclic antidepressant maprotiline to treat depression.

Sometimes cyclic antidepressants are used to treat conditions other than depression, such as obsessive-compulsive disorder, anxiety disorders or nerve-related (neuropathic) pain.

Possible side effects and cautions

Because of the different ways cyclic antidepressants work, side effects vary somewhat from medication to medication. Some side effects may go away after a time, while others may lead you and your doctor to try a different medication. Side effects may also be dependent on the dose, with higher doses often causing more side effects.

Some common possible side effects include:

  • Drowsiness
  • Blurred vision
  • Constipation
  • Dry mouth
  • Drop in blood pressure when moving from sitting to standing, which can cause lightheadedness
  • Urine retention

Other possible side effects include:

  • Weight loss
  • Increased appetite leading to weight gain
  • Excessive sweating
  • Tremor
  • Sexual problems, such as difficulty achieving an erection, delayed orgasm or low sex drive

Generally speaking:

  • Amitriptyline, doxepin, imipramine and trimipramine are more likely to make you sleepy than other tricyclic antidepressants are. Taking these medications at bedtime may help.
  • Amitriptyline, doxepin, imipramine and trimipramine are more likely to cause weight gain than other tricyclic antidepressants are.
  • Nortriptyline and desipramine appear to have better tolerated side effects than other tricyclic antidepressants do.

For antidepressants that cause sleepiness, be careful about doing activities that require you to be alert, such as driving a car, until you know how the medication will affect you.

Which antidepressant is best for you depends on a number of issues, such as your symptoms and any other health conditions you may have. Ask your doctor and pharmacist about the most common possible side effects for your specific antidepressant and read the patient medication guide that comes with the prescription.

Safety issues

Some tricyclic antidepressants are more likely to cause side effects that affect safety, such as:

  • Disorientation or confusion, particularly in older people when the dosage is too high
  • Increased or irregular heart rate
  • More-frequent seizures in people who have seizures

Other issues to discuss with your doctor before you take a cyclic antidepressant:

  • Antidepressants and pregnancy. Talk to your doctor about the risks and benefits of using specific antidepressants. Some antidepressants may harm your baby if you take them during pregnancy or while you're breast-feeding. If you're taking an antidepressant and you're considering getting pregnant, talk to your doctor or mental health professional about the possible risks. Don't stop taking your medication without contacting your doctor first, as stopping might pose risks for you.
  • Drug interactions. When taking an antidepressant, tell your doctor about any other prescription or over-the-counter medications, herbs or other supplements you're taking. Some antidepressants can cause dangerous reactions when combined with certain medications or herbal supplements.
  • Serotonin syndrome. Rarely, an antidepressant can cause high levels of serotonin to accumulate in your body. Serotonin syndrome most often occurs when two medications that raise the level of serotonin are combined. These include other antidepressants, certain pain or headache medications, and the herbal supplement St. John's wort.
    • Signs and symptoms of serotonin syndrome include anxiety, agitation, high fever, sweating, confusion, tremors, restlessness, lack of coordination, major changes in blood pressure and a rapid heart rate.
    • Seek immediate medical attention if you have any of these signs and symptoms.
  • Safety and blood tests. Your doctor may recommend blood levels to determine the most effective dose. Some side effects and benefits of cyclic antidepressants depend on the dose. Overdose of cyclic antidepressants can be dangerous.
  • Chronic health conditions. Cyclic antidepressants can cause problems in people with certain health conditions. For example, if you have glaucoma, an enlarged prostate, heart problems, diabetes, liver disease or a history of seizures, talk to your doctor about whether a cyclic antidepressant is a safe choice for you.

Suicide risk and antidepressants

Most antidepressants are generally safe, but the FDA requires that all antidepressants carry black box warnings, the strictest warnings for prescriptions. In some cases, children, teenagers and young adults under 25 may have an increase in suicidal thoughts or behavior when taking antidepressants, especially in the first few weeks after starting or when the dose is changed.

Anyone taking an antidepressant should be watched closely for worsening depression or unusual behavior. If you or someone you know has suicidal thoughts when taking an antidepressant, immediately contact your doctor or get emergency help.

Keep in mind that antidepressants are more likely to reduce suicide risk in the long run by improving mood.

Stopping treatment with cyclic antidepressants

Cyclic antidepressants aren't considered addictive. However, stopping antidepressant treatment abruptly or missing several doses can cause withdrawal-like symptoms. Symptoms may vary depending on how the drug works. This is sometimes called discontinuation syndrome. Work with your doctor to gradually and safely decrease your dose.

Withdrawal-like symptoms can include:

  • Agitation, irritability or anxiety
  • Nausea
  • Sweating
  • Flu-like symptoms, such as chills and muscle aches
  • Insomnia
  • Lethargy
  • Headache

Finding the right antidepressant

People may react differently to the same antidepressant. For example, a particular drug may work better — or not as well — for you than for another person. Or you may have more, or fewer, side effects from taking a specific antidepressant than someone else does.

Inherited traits may play a role in how antidepressants affect you. In some cases, where available, results of special blood tests may offer clues about how your body may respond to a specific antidepressant. However, other variables besides genetics can affect your response to medication.

When choosing an antidepressant, your doctor takes into account your symptoms, any health problems, other medications you take, and what's worked for you in the past.

Typically, it may take several weeks or longer before an antidepressant is fully effective and for initial side effects to ease up. Your doctor may recommend dose adjustments or different antidepressants, but with patience, you and your doctor can find a medication that works well for you.

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March 30, 2022 See more In-depth

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