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Tricyclic antidepressants and tetracyclic antidepressants

Updated: 07-19-2013

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 They're effective, but they've generally been replaced by antidepressants that cause fewer side effects.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

How tricyclic and tetracyclic antidepressants work

Tricyclic and tetracyclic antidepressants ease depression by affecting naturally occurring chemical messengers (neurotransmitters), which are used to communicate between brain cells.

Cyclic antidepressants block the absorption (reuptake) of the neurotransmitters serotonin (ser-o-TOE-nin) and norepinephrine (nor-ep-ih-NEF-rin), making more of these chemicals available in the brain. This seems to help brain cells send and receive messages, which in turn boosts mood. Most antidepressants work by changing the levels of one or more neurotransmitters.

Cyclic antidepressants also affect other chemical messengers, which can lead to a number of side effects.

Cyclic antidepressants approved to treat depression

Cyclic antidepressants are designated as tricyclic or tetracyclic, depending on the number of rings in their chemical structure — three (tri) or four (tetra). Those approved by the Food and Drug Administration to treat depression are listed below.

Tricyclic antidepressants:

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

Maprotiline is a tetracyclic antidepressant.

Some of these medications are available as liquids (oral solutions).

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

Side effects and cautions

Side effects of cyclic antidepressants vary somewhat from medication to medication and usually don't last long. The most common side effects of cyclic antidepressants include:

  • Dry mouth
  • Blurred vision
  • Constipation
  • Urinary retention
  • Drowsiness
  • Increased appetite leading to weight gain
  • Drop in blood pressure when moving from sitting to standing, which can cause lightheadedness
  • Increased sweating

Other side effects may include:

  • Disorientation or confusion, particularly in older people when the dosage is too high
  • Tremor
  • Increased or irregular heart rate
  • More-frequent seizures in people who have seizures
  • Difficulty achieving an erection, delayed orgasm or low sex drive

Read the package insert for additional side effects and talk to your doctor or pharmacist if you have questions.

Some tricyclic antidepressants are more likely to cause particular side effects. For example, amitriptyline, doxepin and trimipramine are more likely to make you sleepy than are other tricyclic antidepressants. Amitriptyline, doxepin and imipramine are more likely to cause weight gain than are other tricyclic antidepressants. Nortriptyline and desipramine appear to have better tolerated side effects.

Safety concerns

Here are some issues to consider before taking a cyclic antidepressant:

  • Antidepressants and pregnancy. Some antidepressants may harm your child if you take them during pregnancy or while you're breast-feeding. If you're taking an antidepressant and considering getting pregnant, talk to your doctor or mental health provider about the possible dangers. Don't stop taking your medication without contacting your doctor first.
  • Drug interactions. When taking an antidepressant, be sure to tell your doctor about any other medications or dietary supplements you're taking. Some antidepressants can cause dangerous reactions when combined with certain medications or herbal remedies.
  • Serotonin syndrome. Rarely, a cyclic antidepressant can cause dangerously high levels of serotonin. This is known as serotonin syndrome. It most often occurs when two medications that raise 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, sweating, confusion, tremors, restlessness, lack of coordination and rapid heart rate. Seek immediate medical attention if you have any of these symptoms.
  • Safety and blood tests. High doses of tricyclic antidepressants can cause serious health problems. You may need periodic blood tests to check levels of a tricyclic antidepressant in your bloodstream, particularly if you're taking a high dose.
  • Chronic health conditions. Cyclic antidepressants can cause problems in people with certain health conditions. For example, if you have narrow-angle glaucoma, an enlarged prostate, heart problems, liver disease or a history of seizures, talk to your doctor about whether a tricyclic antidepressant is a safe choice for you.
  • Blood sugar and diabetes. Cyclic antidepressants may increase appetite, leading to weight gain — which can affect blood sugar levels, especially in people who have diabetes.
  • Drowsiness. Cyclic antidepressants can make you drowsy and may reduce your ability to drive or use machinery safely. Taking these medications at bedtime may help.

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, but sometimes physical dependence, which is different from addiction, can occur. So stopping treatment abruptly or missing several doses can cause withdrawal-like symptoms. This is sometimes called discontinuation syndrome. Work with your doctor to gradually and safely decrease your dose.

Withdrawal-like signs and symptoms can include:

  • Nausea and vomiting
  • Sweating
  • Flu-like symptoms
  • Lethargy
  • Headache
  • Dizziness
  • Muscle cramping
  • Irregular or rapid heartbeat

Finding the right antidepressant

Each person may react differently to a particular antidepressant and may be more susceptible to certain side effects. Because of this, one antidepressant may work better for you than another, or your doctor may prescribe a combination.

When choosing an antidepressant, your doctor will take into account your symptoms, your health problems, other medications you take, what's worked for you in the past and what's worked for a close relative with depression.

Inherited traits 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 particular antidepressant. The study of how genes affect a person's response to drugs is called pharmacogenomics. However, other variables besides genetics can affect your response to medication.

Typically, it may take several weeks or longer before an antidepressant is fully effective and for initial side effects to ease up. You may need to try several antidepressants before you find the right one, but hang in there. With patience, you and your doctor can find a medication that works well for you.