Tricyclic Antidepressants: Types, Uses, & Side Effects

What Are Tricyclic Antidepressants (TCAs)?

Tricyclic antidepressants (TCAs) are a class of antidepressants and are among one of the first generations of antidepressant drugs developed. TCA drugs are typically the second-line treatment option for depression.

TCAs are considered to be as effective at treating depression as the typical first-line treatment (SSRIs). However, due to a higher instance of side effects, TCAs are typically prescribed after failure to treat depression with SSRIs or if there are initial incompatibilities with SSRI treatment. TCAs may also be prescribed first in cases where specific symptoms, such as chronic pain or sleep disturbances, are also present with depression.^{1, 2}

How Do Tricyclic Antidepressants Work?

While the exact mechanism of TCA drugs is not completely understood, it is known that TCAs work to prevent the absorption of specific chemicals in the brain (neurotransmitters), like serotonin and norepinephrine. This makes these chemicals more available for your brain to use, which helps regulate mood and emotions. Serotonin and norepinephrine also play an important role in improving pain and attention.

In addition, TCAs block binding to other receptors in the body (cholinergic, muscarinic, and histamine). Blocking these additional receptors is believed to contribute to the variety of side effects that can occur with TCAs.^{1, 2, 3}

What Are the Most Common Tricyclic Antidepressants?

Small differences in the chemical structure of TCA drugs can lead to differences in their actions in the body. Some are believed to affect norepinephrine levels, while others may have a stronger effect on raising serotonin levels. The choice between these different types of TCAs depends on the specific symptoms and conditions being treated, as well as individual patient factors.^{2, 4}

Here are the available types of tricyclic antidepressant medications:^{2, 4}

• Amitriptyline (Elavil)
• Desipramine (Norpramin)
• Clomipramine (Anafranil)
• Doxepin (Silenor)
• Imipramine (Tofranil)
• Nortriptyline (Pamelor or Aventyl).
• Protriptyline (Vivactil)
• Trimipramine (Surmontil)
• Amoxapine (Asendin)

Tricyclics Vs. Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are the first-line treatment for depression, while TCAs are the typical second-line treatment. Both of these antidepressants are effective at treating depression. SSRIs work to inhibit serotonin levels by blocking its absorption in the brain. TCAs also work to increase serotonin levels, but they can increase norepinephrine levels as well.

To go along with this, TCAs have actions on several other bodily receptors. These actions bring a higher risk for side effects with TCAs and make it easier to overdose on TCAs if they are used incorrectly.^{2, 3, 4, 5}

What Are Tricyclic Antidepressants Used to Treat?

The first TCA, imipramine, was initially introduced to the market in 1959. Imipramine was approved as an antipsychotic treatment. Over time, the antidepressant effects associated with TCAs were studied, and more TCAs were brought to the market through the years. TCAs were some of the earliest medications used to treat depression.²

Today, most TCAs are FDA-approved as a treatment for depression in adults. Specific TCAs have other approved indications. Clomipramine is approved for use in patients with Obsessive Compulsive Disorder (OCD). Doxepin is approved for use to treat insomnia. Imipramine is approved for use for depression and involuntary urination in childhood.

There are several commonly utilized off-label uses for TCAs, including chronic pain syndrome and anxiety. An off-label use of a medication is a use that is not FDA-approved. Prescribers can decide to use a medication off-label because, in their professional judgment, they believe it may offer a benefit to someone.

Tricyclic antidepressants may be used as an FDA-approved medication to treat:^{1, 6, 7, 8, 9, 10}

• Major depressive disorder (MDD) in adults
• Involuntary urination in childhood
• Insomnia
• Obsessive-compulsive disorder (OCD) in adolescents and adults

Tricyclic antidepressants can also be used off-label (non-FDA approved) for treating:^{2, 3, 4}

• Chronic pain (neuropathic pain, fibromyalgia, etc.)
• Generalized anxiety disorder (GAD)
• Panic disorder
• Bulimia nervosa
• Attention-deficit hyperactivity disorder (ADHD)
• Insomnia
• Migraine prevention

Who Should Not Take Tricyclics?

TCAs are not the right medication for every patient population. People who should avoid TCAs or should use them with caution include children, those with schizophrenia, bipolar disorder, impaired liver or kidney function, pregnant patients, elderly patients, patients who experience seizures, or patients with heart disease. In children and adolescents, similar to other antidepressants, there is a chance of increased suicidal thoughts or actions when taking TCAs. In patients with schizophrenia or manic depression, TCAs can cause manic episodes.

Elderly patients on TCAs can experience orthostatic hypotension (lightheadedness upon standing), which can increase the risk of falls. TCAs can also enhance delirium in elderly patients with preexisting conditions. TCAs are metabolized and cleared through the liver and kidneys, so dosing adjustments should be considered with decreased function of these organs.’

TCAs have been linked to an increased risk of birth defects and should be avoided in pregnant women. TCAs have been shown to cause irregularities in heart rhythm, which are specifically dangerous for those with heart conditions. Lastly, there is an increased risk for seizures when taking TCAs, clomipramine especially, which should be considered in patients with a history of seizures.^{1, 2, 4}

People who may need to avoid taking tricyclic antidepressants include:

• Children and adolescents
• Pregnant women
• People with schizophrenia
• People with bipolar depression
• People with impaired liver or kidney function
• Elderly people
• People with heart disease/conditions
• People who have a history of experiencing seizures

Tricyclic Antidepressant Dosages for FDA-Approved Treatment

The correct dosage of TCAs is unique to each individual. Factors like the diagnosis, age, pre-existing conditions, and past medical history will be used to determine an effective dose for each patient. It is important to note that proper dosage is not determined by the severity of symptoms a patient is experiencing. The individual patient response to the medication helps determine the correct dose, or if dosing adjustments should be made.^{1, 2}

With TCAs, it is necessary to start at a low dose and slowly increase to a higher maintenance dose. This helps lower the risk of adverse events with TCAs. A typical starting dose range when being used for depression ranges from 50-100 milligrams (mg) daily. Common maintenance dosages range from 100-300 mg daily considering the patient’s response. Note that protriptyline (Vivactil) starting and maintenance dosages are notably lower, with a starting dose range of 15-30 mg daily and a maintenance dose of 30-60 mg daily. Off-label uses of TCAs commonly require lower maintenance doses when compared to FDA-approved uses.^{1, 2, 3, 4}

Forms & Strengths of Tricyclic Antidepressants

The most common route for TCAs is either oral tablets or capsules. Doses can vary greatly depending on past medical history, the condition being treated, and individual patient’s reaction. These tablets and capsules range from 3-150 mg, which allows prescribers great flexibility with possible doses.

Silenor (name-brand doxepin) is in the low dosage of 3 and 6 mg tablets. This dosage form is used specifically to treat insomnia. TCA tablets and capsules are immediate-release forms. This means they begin to get absorbed into the body immediately, and they reach their highest concentration anywhere between 2-8 hours, depending on the patient and specific TCA.⁶

For those who may not be able to swallow a pill or capsule, there are solutions and concentrated solution forms available. These forms are commonly useful in children or elderly patients. However, only select TCAs are available in liquid formulations. There are also topical doxepin creams that are used to relieve itchiness associated with eczema.⁷

Tricyclic antidepressants are available in the following forms and strengths:

• 3 milligrams (mg) oral tablet (Silenor only)
• 6 mg oral tablet (Silenor only)
• 5 mg oral tablet (protriptyline only)
• 10 mg oral tablet
• 25 mg oral tablet
• 50 mg oral tablet
• 75 mg oral tablet
• 100 mg oral tablet
• 150 mg oral tablet
• 10 mg oral capsule
• 25 mg oral capsule
• 50 mg oral capsule
• 75 mg oral capsule
• 100 mg oral capsule
• 125 mg oral capsule
• 150 mg oral capsule
• 10 milligram/5 milliliters (mg/mL) oral solution
• 10 milligram/milliliter (mg/mL) oral concentrated solution
• 5 grams/100 grams (5%) topical cream (doxepin only)

What Happens If I Miss a Dose of Tricyclic Antidepressants?

If you miss a dose of a TCA, the time when you realize you’ve missed the dose is important. If you realize soon after your regularly scheduled dose, you can take the regular dose of your medicine. If it is not close to the regular time of your dose, wait until your next regular dose to take the medication. If you are unsure about the timing, it is best to contact your doctor or pharmacist about when to take the next dose. It is important that you do not take extra medicine to catch up with the last dose.⁸

If you wish to stop taking your TCA medication, do not to stop abruptly. Abruptly stopping a TCA can lead to withdrawal effects such as nausea, vomiting, diarrhea, trouble sleeping, sweating, or irritable mood. You should talk with your doctor or pharmacist if you would like to stop taking your TCA, and they can help determine a plan to slowly taper you off of this medication.^{4, 8}

Tricyclic Antidepressant Side Effects

TCA medications have a relatively wide variety of possible side effects due to their actions on several different body receptors. TCAs can have effects on the cardiovascular (heart and blood) system, the central nervous system (brain), digestive system, hormonal system, parasympathetic nervous system (“rest and digest” functions), along with various other bodily functions. Each TCA interacts with bodily receptors uniquely. This makes certain TCA side effects more tolerable than others.^{1, 2, 4}

Common Side Effects of Tricyclic Antidepressants

The most commonly reported side effects for TCAs include drowsiness, dry mouth, difficulties urinating, constipation, or dizziness upon standing. The severity of these side effects depends on the patient’s response and dosage. Talk with your doctor or pharmacist if you have side effects that are not tolerable to discuss possible dosing adjustments or alternative treatment options.^{1, 2, 3, 4}

Common side effects of the most common TCA drugs include:^{1, 2}

• Dry mouth
• Nausea
• Dizziness
• Constipation
• Urinary retention
• Sedation
• Increased heart rate
• Confusion

Serious Side Effects of TCAs

TCAs are also associated with some more serious side effects. You should seek medical attention right away if you are taking a TCA and experience any serious side effects. This could include things like irregular heartbeats, allergic reactions, seizures, or irregular mood/behaviors. It is important to seek medical attention to get serious adverse effects under control as soon as possible.^{1, 3, 4}

Serious side effects of tricyclic antidepressants may include:^{1, 2, 3, 4, 11}

• Suicidal thoughts or behaviors
• TCA-induced mania
• Seizures
• Heart irregularities
• Allergic reactions
• Antidepressant withdrawal
• Serotonin syndrome
• Liver failure

Tricyclic Antidepressant Discontinuation

If you abruptly stop taking a TCA, you could experience antidepressant discontinuation syndrome. This is caused by the body’s withdrawal response after discontinuing antidepressants. Some common withdrawal symptoms include irritability, anxiousness, trouble sleeping, nausea, vomiting, and sweating. These symptoms can be reduced by slowly tapering off of the antidepressants. This is why it is important to talk with your doctor or pharmacist to plan a safe approach for discontinuing your TCA medication.⁸

Tricyclic Antidepressants Warnings & Precautions

TCAs can be an effective treatment for some, but there are precautions to consider with their use. Some populations can be more susceptible to side effects depending on their past medical history and individual reactions to TCA medications.

There are also some general concerns to look out for when starting or changing doses of TCA medications. One major warning is the possibility of increased suicidal ideation that is possible for those taking TCAs and other antidepressants. You should make sure your doctor or pharmacist has an accurate medical history and current medication list to allow them to provide their best judgment.^{1, 2, 3, 4}

Warnings and precautions for taking tricyclic antidepressants include:^{1, 2, 3, 4}

• Increased risk of suicidal thoughts: For some, suicidal ideation can occur. This is especially apparent for children, adolescents, or young adults.
• A diagnosis of bipolar disorder (BP): For people with bipolar disorder, TCAs and other antidepressants can lead to a shift towards mania or hypomania. Hypomania and mania are marked by very elevated mood and energy, over-active behaviors, increased confidence, and feeling undefeatable.
• Allergic reactions: Rarely, people can have a severe allergic reaction when taking TCA medication that requires immediate medical attention. If you are allergic to a TCA or any of its inactive ingredients, you should avoid taking these medications.
• A history of heart problems or heart attack: Due to possible side effects on heart rhythms, TCAs should be used with caution in people with a history of heart problems. TCAs must be avoided altogether in patients who have recently had a heart attack.
• Older age: TCA side effects can be more problematic for older populations, especially dizziness upon standing, which can pose a fall risk.
• History or current diagnosis of glaucoma: TCAs can cause increased inner eye pressure, which can be problematic for those with glaucoma.
• TCA-induced mania: For some populations, TCAs can induce manic episodes marked by a shift to an extremely happy mood, sleeping less, or feeling invincible. This includes older populations with pre-existing mental conditions and people with bipolar disorder.
• Increased risk of seizures: TCAs can lower the seizure threshold and need to be closely monitored in those with a history of seizures.
• Serotonin syndrome: This is a serious reaction that occurs when the level of serotonin is too high in the body. Symptoms of serotonin syndrome include diarrhea, shivering, muscle stiffness, fever, or seizures.
• Liver failure: TCAs can affect liver functioning, which can lead to failure for some more susceptible patients. Signs of possible liver failure are yellowed skin/eyes, nausea, vomiting, pain in the upper right abdomen, confusion, or disorientation.

What to Avoid When Taking Tricyclic Antidepressants

TCAs can interact with many body receptors, which makes their use not compatible with a few different classes of medications. In general, the use of TCAs with antidepressants needs to be closely monitored to avoid elevated serotonin levels in the brain. Other antidepressants, especially monoamine oxidase inhibitors (MAOIs), should not be used at the same time as TCA therapy. Some types of drugs are not compatible with TCA use because they are broken down in the body the same way as TCAs. This can affect the concentration of drugs in the body and contribute to significant adverse effects.^{1, 2}

TCAs can also interact with other substances, like herbal medications, alcohol, over-the-counter medications, certain laxatives, and illegal drugs. It is important to consider all different substances when talking to your healthcare team about TCA therapy. This will help avoid interactions with TCA therapy and minimize the side effects that can come with it.^{1, 2, 4, 9, 10}

Eight substances you should avoid while taking tricyclic antidepressants include:^{1, 2, 4, 9, 10}

• Monoamine oxidase inhibitors (MAOIs): MAOIs, another type of antidepressant, should not be used during TCA therapy as their use together has caused high fever, convulsions, and even death. With other antidepressants, close monitoring is required to prevent adverse effects.
• Topamax (topiramate): When taking TCAs with topiramate, significantly higher concentrations of TCA in the blood have been reported.
• Drugs metabolized by P450 2D6 (e.g. amitriptyline): This is the specific route in your metabolism that is used to clear TCAs from your body, so using more than one medication that is cleaned out the same way can overwhelm your body.
• Cisapride (Prepulsid or Propulsid): When combining cisapride and TCAs, the risk for irregular heartbeats is elevated.
• Alcohol: Drinking alcohol while taking TCAs can result in dizziness and drowsiness. Additionally, alcohol is not recommended for those struggling with depression in general, as it can make depressive symptoms worse.
• St. John’s wort: This herbal supplement has many different drug interactions, including TCAs, antihistamines, immunosuppressants, and hormonal birth control. St. John’s wort can alter the blood concentration of TCAs, possibly contributing to negative outcomes with TCA therapy.
• Azelastine (nasal spray): This medication combination can increase the severity of adverse effects of TCAs and should be avoided.
• Kratom: Kratom is an over-the-counter supplement used as a pain reliever. When combined with TCAs, it can increase adverse effects like slowed breathing, low blood pressure, and confusion.

Can You Overdose on Tricyclic Antidepressants?

Yes, you can overdose on TCA medications. TCAs are the most common antidepressants seen in fatal overdose cases, and a person should seek medical help right away if there is a suspected overdose.

Some major signs of overdose include irregular heart rhythms, coma, very low blood pressure, or involuntary muscle contractions. Some people experience temporary visual hallucinations, nausea and vomiting, confusion, dizziness, dilated pupils, fever, and other adverse effects during an overdose. The symptoms can develop rapidly, so it is important to act quickly if there is a suspected overdose.^{1, 2, 4}

What Should You Do If You Take Too Much Tricyclic Antidepressant Medication?

If you suspect that you or someone around you has taken too much of a TCA medication, you should seek medical help right away. Call 911 or your local poison control center right away (800-222-1222). From there, you should listen to any instructions they provide you while you wait for help to arrive. It may be helpful if you have information on the person, such as current medications, medical conditions, amount of medication(s) consumed, etc., ready for medical providers to be aware of.⁹

Questions to Ask Your Healthcare Provider About Tricyclic Antidepressants

If you are interested in TCA therapy, it is important to weigh the pros and cons of these medications. Speaking with your doctor, pharmacist, psychiatrist, or therapist about possible outcomes and side effects with TCAs should be used to inform this decision. If you are struggling with mental health and do not have a therapist (or are not achieving your goals with your current therapist), consider finding the right therapist, as it may be a beneficial treatment option.

Questions to ask your care team about tricyclic antidepressants include:

• Is there anything I should tell my therapist about this new medication?
• What is the best dosage to ensure fewer side effects?
• Am I at risk for more severe symptoms if I am already taking other anxiety /depression medications?
• How long should it take for me to notice the benefits of a TCA?
• Are there any drugs that I am currently taking that could negatively react with a TCA?
• What should I use along with a TCA medication to treat depression?
• When should I reach out to you if I am experiencing side effects with a TCA?
• How long is the typical duration of TCA treatment?
• Who should I inform if I start a new TCA prescription?
• Will my insurance cover a prescription for a TCA medication?
• Are there any dietary restrictions to consider while taking a TCA?
• What kind of follow-up appointments are necessary when first being prescribed a TCA?
• Is it safe to take alcohol with amitriptyline or other TCAs?

How to Get a Tricyclic Antidepressant Prescription

If you feel that TCAs may be a good treatment option for you, talk with your doctor, pharmacist, therapist, or psychiatrist about what to consider before taking TCA medications. You should be prepared to discuss medical history, any current conditions, current medications, and more to determine if TCA therapy could be effective for you. For some, using an online psychiatry service may be a more accessible way to discuss treating depression.