Drug Info

What are tricyclic antidepressants?

Cropped SingleCare logo By | Updated on September 24, 2020
Medically reviewed by Karen Berger, Pharm.D.

Picture a city from a bird’s eye view, surrounded by bridges, with a constant stream of cars arriving and leaving. Each car carries people who complete certain activities and deliver certain messages. This is how neurotransmitters interact within our brain cells. But what happens when certain bridges close and cars can leave, but not arrive? 

This illustration is pretty basic, but it gives a sense of how mental illnesses like depression or bipolar disorder might look in the brain. Neurotransmitters influence everything from mood to movement, so a lack or abundance can have detrimental effects. Too many cars leaving reduces activity in the city. Too many cars arriving makes it incredibly busy.

Cyclic antidepressants change the brain’s circuitry to help to correct these imbalances. Developed in the late 1950s, tricyclic antidepressants (TCAs) were a popular medication for depression and obsessive-compulsive disorder (OCD). But their popularity waned in the late 1980s as their potential side effects piled up, and the newer antidepressants (selective serotonin reuptake inhibitors, or SSRIs) gained traction.

Here is a guide to tricyclic antidepressants and their side effects.

How tricyclic antidepressants work

Even though we don’t have a comprehensive understanding of how the brain works, many experts agree that depression and other mental health conditions stem from chemical imbalances. This broad term—chemical imbalances—describes any lack or abundance of neurotransmitters.

Depression is a complex medical condition. Depression is due to an imbalance of neurotransmitters, like serotonin, but it involves many more contributing factors, such as stress, genes, and medications. 

Serotonin is the “feel-good” chemical that regulates mood, promotes a sense of calm, and helps you sleep. Norepinephrine, which is also known as noradrenaline increases energy and attention while regulating stress reactions. 

The way that tricyclic antidepressants (TCAs) work is not completely understood. They are thought to inhibit the reuptake of serotonin and norepinephrine. 

What does that mean? It means that more serotonin and norepinephrine are available to do their jobs of helping your mood and energy. Other neurotransmitters, like acetylcholine, may be involved in the process too, depending on the particular medication.

What they’re used for

By altering the brain’s concentration of these chemical messengers, tricyclic antidepressants can effectively treat major depressive disorder and other conditions like:

  • Bipolar disorder
  • Obsessive-compulsive disorder (OCD)
  • Generalized anxiety disorder (GAD)
  • Panic disorder
  • Persistent depressive disorder, also known as dysthymia (a mild, long-term form of depression)
  • Post-traumatic stress disorder (PTSD)
  • Insomnia

Tricyclic antidepressants can treat chronic nerve pain, too. “After direct pain medicines (opioids and NSAIDs), there are no better medicines for chronic pain than TCAs,” says Mark Rego, MD, an assistant clinical professor of psychiatry at the Yale University School of Medicine. “They are also the best medicine for neuropathic pain from conditions like diabetes or after shingles [postherpetic neuralgia].” 

In most cases, tricyclic antidepressants are considered safe. However, there are numerous tricyclic antidepressant side effects, including serious ones like suicidal thoughts, warranting a black box warning from the United States Food and Drug Administration (a requirement for antidepressants). Consequently, healthcare providers now typically prescribe them as a last resort, after other treatments have failed.

Even so, “there are various groups of people, especially people with longstanding chronic depression (people who never feel normal) who are difficult to treat,” says Dr. Rego. “These people often respond to tricyclic antidepressants. Tricyclic antidepressants are very different from everything we commonly use, so people who do not do well with common meds often do well with them.”

Currently, the most common replacements for tricyclic antidepressants as a treatment of depression are SSRIs. Tricyclic antidepressants can affect not just serotonin and norepinephrine, but a host of other neurotransmitters, giving rise to a wider range of potential side effects. SSRIs, on the other hand, pinpoint serotonin, reducing the risk of some side effects. So, SSRIs are often considered a safer choice. 

Tricyclic antidepressants list

When it comes to tricyclic antidepressants, healthcare providers have a handful of options. They include:

Or, a healthcare provider might prescribe a tetracyclic antidepressant instead. Tetracyclic antidepressants are similar in function to tricyclic antidepressants, but they have different chemical structures—containing four rings of atoms instead of three. Tetracyclic antidepressants include:

How does the doctor decide which medicine to prescribe? It depends on the condition they’re treating. Tricyclic antidepressants are most commonly prescribed for depression but can be useful in treating numerous other conditions (see the list above). 

It’s a versatile drug, so different conditions respond well to different tricyclic antidepressants. Parool Desai, ARNP, a psychiatric nurse practitioner at Clarity Health Solutions, often prescribes them for various purposes. “I find these tricyclics like amitriptyline effective for challenging OCD cases,” she says. “To treat insomnia issues, I prescribe doxepin, and imipramine is effective to treat urinary incontinence and sleep issues.”

Side effects of tricyclic antidepressants

Because tricyclic antidepressants can affect many neurotransmitters, they can potentially cause a broad scope of side effects. The most common are:

  • Drowsiness
  • Blurred vision
  • Dry mouth
  • Constipation
  • Increased appetite
  • Weight gain 
  • Muscle twitches or tremors
  • Sweating
  • Hives
  • Rash
  • Low blood pressure (can cause lightheadedness when standing up quickly) or high blood pressure

Tricyclic antidepressants have also been linked to the side effect of urinary retention (difficulty urinating). Prescribers sometimes use this side effect as an advantage to treat incontinence caused by an enlarged prostate. 

Tricyclic antidepressants can also cause increased heart rate or irregular heart rhythms. And in some cases, they’re responsible for erectile difficulties and other types of sexual dysfunction

Anyone considering tricyclic antidepressants should speak with a healthcare professional about these potential side effects before beginning treatment. This pretreatment conversation should also include discussion about family history, medical history, other medications, and pregnancy plans. Your healthcare professional can provide medical advice about how to avoid specific side effects altogether.

Because tricyclic antidepressants can worsen certain conditions, anyone with a heart condition, liver condition, glaucoma, enlarged prostate, diabetes, or who is pregnant should consult their provider before taking a tricyclic antidepressant. 

Drug interactions

Additionally, tricyclic antidepressants can interact with particular prescription or over-the-counter medications, such as:

  • Tagamet (cimetidine)
  • Monoamine oxidase inhibitors (MAOIs)
  • Zyvox (linezolid)
  • Epinephrine
  • Solid forms of potassium

The interactions can be severe, so providers will ask about any concurrent medications before prescribing tricyclic antidepressants. 

You should avoid alcohol if you are taking a tricyclic antidepressant. The combination of alcohol and a TCA can cause additive side effects like respiratory depression (your breathing could slow or even stop), central nervous system (CNS) depression (causing dizziness, drowsiness, impairment leading to accidents), and low blood pressure.

Other drug interactions may occur. Consult your healthcare provider to ensure that all of the prescription and over-the-counter medications you take are safe to take with a tricyclic antidepressant.

Withdrawal symptoms

Once someone begins a course of antidepressant treatment, it’s not always easy to stop. Quitting cold turkey after six or more weeks of treatment causes antidepressant discontinuation syndrome in 20% of patients. This type of withdrawal can include symptoms like:

  • Nausea
  • Vomiting
  • Headache
  • Chills
  • Irritability
  • Anxiety
  • Muscle aches
  • Insomnia
  • Dizziness 
  • Tremors 
  • Restlessness
  • Hallucinations 

Antidepressants and suicide risk

In 2004, the FDA slapped a black box warning on antidepressants, including tricyclic antidepressants and SSRIs. This is the highest grade of FDA warning, one acknowledging a drug’s potentially life-threatening side effects—in this case, suicidal thoughts and actions. 

Certain studies discovered an increase in suicidal ideation among people taking tricyclic antidepressants and SSRIs. A 2005 study found a correlation between tricyclic antidepressant prescriptions and higher suicide rates, and a 2012 study from the International Journal of Toxicology determined that even though there was a link between antidepressants and suicidal thoughts, SSRIs were slightly safer than tricyclic antidepressants in this respect. 

Suicidal ideation as a side effect is more prevalent in children, adolescents, and young adults. Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. Although the risk of suicidal thoughts or behavior is higher in younger patients, patients of any age should be closely monitored for signs such as changes in behavior or mood.

Four percent seems like an incremental risk, but it’s pretty significant when considering the potential consequences. It’s critical to speak openly with medical and mental health professionals before starting treatment. 

Preventing suicide

If you or someone you know is experiencing suicidal thoughts, help is available. Call the National Suicide Prevention Hotline at 800-273-8255, where professionals are available 24/7 to talk and provide emotional support. 

Looking for early warning signs is perhaps the most effective method of suicide prevention. It can sometimes be challenging to recognize when someone is considering suicide, but here are some common symptoms:

  • Isolation and withdrawing from social interaction
  • Extreme mood swings
  • Giving away belongings
  • Engaging in reckless behavior
  • Talking about hopelessness or self-harm
  • Sleeping too much or too little
  • Increased drug or alcohol use
  • Obtaining the means for attempting suicide (buying a gun, etc.)
  • Saying goodbye to loved ones

If you recognize these signs in yourself or someone else, seek immediate help from a trained mental health professional or call the National Suicide Prevention Hotline. If you find someone who has attempted suicide, take the following actions:

  • Stay with the person.
  • Call 911 or take them to the nearest emergency room.
  • Call a friend or family member to inform them of the situation.