Tricyclic Antidepressants (TCAs): A Complete Guide

Tricyclic antidepressants, or TCAs, are a type of antidepressant. Developed in the middle of the 20th century, TCAs were some of the first prescription medications approved by the FDA to treat major depression and related conditions.

Although tricyclic antidepressants were commonly used throughout the 20th century, they have largely been replaced by newer types of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

Today, TCAs are used by millions of people every year in the United States. They’re generally prescribed to treat depression when newer medications aren’t completely effective, such as for people with treatment-resistant depression.

If you’ve been diagnosed with depression and haven’t experienced improvements after taking an SSRI, your healthcare provider may suggest a tricyclic antidepressant as an alternative.

Below, we’ve listed the most common TCAs that are still in use today. We’ve discussed how antidepressants of this type work, as well as the potential side effects you may experience if you’re prescribed one.

Finally, we’ve answered some of the most common questions about tricyclic antidepressants, from how long they take to work to treat depression to potential drug interactions, safety and what you should know before stopping this type of drug.

Tricyclic antidepressants were some of the first medications produced to treat major depressive disorder (MDD, or clinical depression).

The first TCAs were developed in the 1950s. Imipramine, an early TCA, was developed in the 1950s and approved in 1959 by the Food and Drug Administration (FDA). Amitriptyline, a TCA marketed under the brand name Elavil®, was approved in the 1960s by the FDA.

During the 20th century, many healthcare professionals prescribed TCAs as a typical treatment for depression. Certain types of TCAs are currently prescribed or have been used in the past to treat: 

• Major depressive disorder and other forms of depressive illness

• Some anxiety disorders, including generalized anxiety disorder (GAD), social anxiety disorder (SAD) and obsessive-compulsive disorder (OCD) 

• Insomnia and other sleep-related disorders

• Post-traumatic stress disorder (PTSD)

• Eating disorders, such as bulimia nervosa 

• Borderline personality disorder (BPD)

• Migraines and persistent headaches

• Certain forms of pain, including neuropathic pain conditions

• Attention-deficit hyperactivity disorder (ADHD)

Some historical and current uses of tricyclic antidepressants are off-label, meaning they are not for the medication’s original FDA-approved purpose. For example, some TCAs are prescribed to people off-label to treat issues such as insomnia and chronic pain.

Most antidepressants, including tricyclic antidepressants, work by increasing levels of natural chemicals, called neurotransmitters, that are involved in managing aspects of your mood and personality.

Neurotransmitters are used to control a large range of biological functions. Neurotransmitters help to manage everything from your energy levels and alertness to your ability to fall and stay asleep, your sex drive, your appetite and more.

More specifically, tricyclic antidepressants function by increasing levels of the neurotransmitters serotonin and norepinephrine.

Serotonin, which is sometimes referred to as the “happiness chemical,” is one of a large variety of neurotransmitters that are used to transmit signals between your neurons, or nerve cells.

Although serotonin is commonly associated with happiness, its real role in the body is far more complicated. For example, serotonin helps to regulate your mood and anxiety levels. It’s also a key neurotransmitter for regulating your digestive health, sleep patterns and bone health.

Research shows that depressed people often have low levels of serotonin transmission -- a fact that’s an important part of the “serotonin theory” of depression, which suggests that low levels of serotonin are a potential cause of depression.

Like serotonin, norepinephrine is another important neurotransmitter that’s involved in managing your moods and feelings.

Also referred to as noradrenaline, it’s responsible for increasing heart rate and blood pressure. It also plays a role in your sleep-wake cycle, your ability to focus on key tasks and in your ability to store information as memories.

Low levels of norepinephrine are linked to a reduced ability to concentrate, lethargy (low energy levels) and certain other aspects of depression.

Tricyclic antidepressants work by blocking the reuptake of these neurotransmitters. This leads to an increase in serotonin and norepinephrine levels that, for many people, helps to relieve the symptoms of depression. 

Tricyclic antidepressants are common, widely used medications. Because of their age, many of the most common tricyclic antidepressants are sold as brand name medications and as generic medications under a variety of different names.

Tricyclic antidepressants include:

• Amitriptyline. Sold under the brand name Elavil®, amitriptyline is prescribed to treat depression. It’s also used off-label for other health conditions, including chronic pain and irritable bowel syndrome.

• Amoxapine. Sold under the brand name Asendin®, amoxapine is generally prescribed as a second or third-line treatment for persistent depression and depression that doesn’t improve with other medications.

• Desipramine. Sold under the brand names Norpramin® and Pertofrane®, desipramine is prescribed to treat depression. It’s also occasionally used off-label as a treatment for ADHD, bulimia nervosa, irritable bowel syndrome and bladder control problems.

• Doxepin. Sold under the brand names Sinequan® and others, doxepin is prescribed to treat depression and anxiety.Doxepin is also marketed as a treatment for sleeping disorders such as insomnia under several brand names, including Silenor®.

• Imipramine. Sold under the brand name Tofranil®, imipramine is typically used to treat severe depression with melancholic and atypical features. It’s also used in children as a medication for preventing nocturnal enuresis (bet wetting).

• Nortriptyline. Sold under the brand name Pamelor®, nortriptyline is prescribed to treat depression.

• Protriptyline. Sold under the brand name Vivactil®, protriptyline is prescribed to treat depression, narcolepsy, anxiety, headaches and ADHD. It has fewer sedative effects than other TCAs.

• Trimipramine. Available under the brand name Surmontil®, trimipramine is prescribed to treat depression. It may also be prescribed off-label to treat anxiety and as a sleep aid.

A few decades ago, many of these medications were typically prescribed as first-line treatments for depression. 

However, due to their relative side effect risk compared to newer antidepressants, few are used as first-line treatment options for depression today. 

However, your healthcare provider may prescribe one of the medications listed above in certain circumstances, such as: 

• If you haven’t responded to newer antidepressants. For some people, TCAs reduce the symptoms of depression when newer medications, such as SSRIs or SNRIs, aren’t effective.

• For conditions other than depression. Some TCAs are still prescribed, either on-label or off-label, to treat other mental disorders and physical health issues, such as insomnia, bipolar disorder and certain forms of anxiety.

Almost all tricyclic antidepressants come in tablet or capsule form. Depending on the medication and dosage you’re prescribed, you may need to take your tricyclic antidepressant one or several times per day.

Follow the instructions provided by your healthcare provider and use your medication exactly as prescribed. 

Antidepressants, including tricyclic antidepressants, may take several weeks to start working as a form of treatment for depression. You may notice your sleep, appetite and ability to focus on specific tasks improving before you experience any changes in your moods and feelings.

It’s important to continue using your medication as prescribed during the first few weeks, even if you don’t notice any immediate improvements. 

If you don’t notice any change in your mood, appetite, or energy levels after taking your tricyclic antidepressant for several weeks, talk to your healthcare provider. Do not make any changes to your medication usage or dosage without first consulting your healthcare provider. 

Compared to newer antidepressants, such as SSRIs and SNRIs, tricyclic antidepressants tend to cause more side effects. Many TCAs are no longer used as first-line depression treatments specifically because of their side effect risk. 

The side effects you might experience can vary based on the type of TCA you’re prescribed, its dosage and other factors. Some side effects may become less severe or disappear on their own over time. However, others can be persistent. 

Common side effects of tricyclic antidepressants include:

• Blurred vision 

• Confusion 

• Constipation 

• Dizziness 

• Drowsiness 

• Xerostomia (dry mouth)

• Hyperhidrosis (excessive sweating) 

• Orthostatic hypotension (sudden drop in blood pressure after standing up)

• Sexual side effects, such as reduced sex drive, erectile dysfunction and difficulty or delay in reaching orgasm 

• Urinary retention 

• Weight gain and increased appetite

If you experience adverse effects from TCAs, you may need to try several medications before finding one that works best for you. 

Some tricyclic antidepressants can cause cardiovascular side effects, including arrhythmia (an irregular heartbeat). In people with heart disease caused by narrowed heart arteries, TCAs can potentially cause severe cardiovascular issues such as sudden cardiac death (SCD).

Make sure to tell your healthcare provider if you have any history of heart disease before using any type of tricyclic antidepressant.

Like other antidepressants, TCAs can also contribute to an elevated risk of suicidal thoughts or behavior in people aged 24 and under. We’ve discussed this safety issue in more detail in the section below.

If you develop persistent, severe or intolerable side effects after using a tricyclic antidepressant, talk to your healthcare provider. Your healthcare provider may suggest adjusting your dosage or switching to a more tolerable antidepressant.

Tricyclic antidepressants are usually safe medications when they’re taken as prescribed by your healthcare provider. However, like other medications, there are certain side effects, interactions and other potential safety issues that you should be aware of if you’re prescribed a TCA.

Some Tricyclic Antidepressants Can Cause Drowsiness

Drowsiness is a common side effect of tricyclic antidepressants, and it may be more severe with some medications than with others. In fact, some tricyclic antidepressants are even marketed as sleep aids due to their sleep-inducing effects. 

For example, the tricyclic antidepressant doxepin is marketed under the brand name Silenor as a medication for treating insomnia.

After taking your medication, you may feel more tired than normal. Research suggests that the effects of some tricyclic antidepressants on drowsiness, such as amitriptyline, protriptyline and protriptyline, usually begin 90 minutes after ingestion and can last for several hours.

If you’re prescribed a tricyclic antidepressant that can cause drowsiness, pay close attention to your response to the medication before driving a vehicle or performing any other activities that require alertness. 

Tricyclic Antidepressants Can Cause Drug Interactions

Tricyclic antidepressants can interact with other medications and substances, including other prescription medications, medications available over the counter and some herbal and dietary supplements. 

TCAs may interact with other antidepressants, medications that affect cytochrome P450 (CYP) isoenzymes and medications that contain epinephrine or increase epinephrine levels, such as EpiPen® and similar devices used to treat allergic reactions.

Using tricyclic antidepressants with medications that contain epinephrine or increase levels of epinephrine in the body may lead to unsafe epinephrine levels and increased effects on blood pressure and heart rate.

Before you use any type of antidepressant, make sure that you inform your healthcare provider about all medications, supplements and health products that you currently use.

Some Interactions Involving TCAs Can Be Life-Threatening

Some interactions involving tricyclic antidepressants can cause serotonin syndrome -- a serious, potentially life-threatening condition caused by excessively high levels of serotonin.

The symptoms of serotonin syndrome include an altered mental state, overactive reflexes and a high body temperature. When severe, serotonin syndrome can be life threatening.

Serotonin syndrome can occur when you use tricyclic antidepressants at the same time as other medications that increase serotonin levels, including other antidepressants, herbal supplements such as St. John’s wort and certain opioid and non-opioid medications for pain relief.

To avoid serotonin syndrome, do not use TCAs with other medications that increase your levels of serotonin. Make sure to inform your healthcare provider about all medications or supplements you currently use or have recently used before using any TCA.

It’s especially important to be careful with monoamine oxidase inhibitors (MAOIs), another older class of antidepressants that can remain active in the body for several weeks.

Make sure to tell your healthcare provider if you’ve previously used an MAOI to treat depression or a related condition, especially during the past few weeks.

Tricyclic Antidepressants May Worsen Certain Health Conditions

Tricyclic antidepressants may worsen some health conditions, including heart disease and other cardiovascular issues, as well as conditions that affect the liver. Some evidence suggests that TCAs may increase the risk of seizures in people with epilepsy.

Furthermore, TCAs can potentially cause serious issues such as acute ocular crisis when used by people with angle-closure glaucoma.

If you have any preexisting medical conditions, it’s important to inform your healthcare provider before using any type of TCA or other medication to treat depression.

TCAs Are Generally Not Considered Safe During Pregnancy

TCAs are not considered safe in pregnancy and are linked to congenital defects, including eye, face, neck and ear defects. Women who are pregnant or planning to become pregnant should carefully discuss the use of TCAs or other antidepressants with their healthcare provider.

With the exception of doxepin, research has not found a link between the use of TCAs and any significant adverse effects while breastfeeding. 

TCAs Can Increase Suicide Risk in Young People

Research has found that antidepressants, including TCAs, can contribute to an increased risk of suicidal ideation and behavior in people aged 24 and under. Like other antidepressants, TCAs carry a “black box” warning from the FDA notifying users of these risks.

If you’re prescribed any type of antidepressant and are under the age of 24, make sure to stay alert and seek immediate help from your healthcare provider if you notice any sudden changes in your mood or develop suicidal thoughts.

If you ever feel suicidal, you can get help by calling the National Suicide Prevention Lifeline at 1-800-273-8255.

Suddenly Stopping a TCA May Cause Withdrawal Symptoms

If you’re prescribed a tricyclic antidepressant and feel like it isn’t working, or if you have severe or persistent side effects that are affecting your quality of life, it’s important not to suddenly stop taking your medication without talking to your healthcare provider first.

When stopped abruptly, TCAs can cause antidepressant discontinuation syndrome -- a group of withdrawal symptoms that may include insomnia, flu-like symptoms, nausea, irritability, sensory disturbances and imbalance.

If you want to stop taking your antidepressant, talk to your healthcare provider first. They’ll help you to gradually and safely reduce your dosage to avoid withdrawal symptoms.

Because of their side effect risks, tricyclic antidepressants are usually only prescribed if newer antidepressants are not effective. Before prescribing a tricyclic antidepressant, your healthcare provider may recommend one of the following medications:

• Selective serotonin reuptake inhibitors (SSRIs). SSRIs work by increasing levels of serotonin. They’re a newer class of drugs than tricyclic antidepressants and are usually the first type of medication prescribed for the treatment of depression.SSRIs generally have fewer side effects than TCAs and other older medications used to treat depression.

• Serotonin-norepinephrine reuptake inhibitors (SNRIs). SNRIs work by increasing the levels of serotonin and norepinephrine, a second neurotransmitter that’s associated with depression symptoms.

• Monoamine oxidase inhibitors (MAOIs). MAOIs are an older class of antidepressants that, like TCAs, were developed in the mid-20th century. They have a significant risk of causing side effects and interactions and are rarely used as first-line treatments.Your healthcare provider may prescribe a monoamine oxidase inhibitor if SSRIs or other more modern antidepressant treatments aren’t effective.

How Long Do Tricyclic Antidepressants Take to Work?

Although tricyclic antidepressants are generally effective at treating depression, it’s uncommon to notice an immediate improvement within a few days of using medication. 

Like other antidepressants, most TCAs take several weeks to start working. You may notice an improvement in your appetite, sleep habits or cognitive function before you experience changes in your moods and feelings after starting treatment with antidepressants.

If you don’t notice improvements within a few weeks of starting an antidepressant, talk to your healthcare provider. Your healthcare provider may suggest adjusting your dosage or switching to a different type of medication. 

How Long Do You Need to Take Tricyclic Antidepressants?

Since the type and severity of depression can vary from person to person, there’s no set amount of time for which you’ll need to take tricyclic antidepressants.

It’s important to continue taking tricyclic antidepressants for as long as is recommended by your healthcare provider.

Many people notice improvements after taking antidepressants for several months. It’s common to feel as if you can stop taking your medication at this point, as your depression symptoms may have become less severe and noticeable. 

Prematurely stopping treatment with any type of antidepressant is not recommended. Doing so may cause your depression to return. It often takes six to 12 months of treatment for people to successfully overcome depression using antidepressants.

If you’re prescribed a tricyclic antidepressant and want to know how long you’ll need to continue using it, talk to your healthcare provider. 

What Are The Differences Between Tricyclic Antidepressants and SSRIs?

Although tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) are both used to treat depression, there are several differences between them:

• Both medications treat depression, but through different mechanisms of action. Tricyclic antidepressants act on approximately five neurotransmitter pathways to inhibit serotonin and norepinephrine reuptake.SSRIs target serotonin more specifically by blocking its reuptake. Both medications are used to increase serotonin levels and can help to treat depression.

• Tricyclic antidepressants are much older than SSRIs. The first TCAs were developed in the 1950s, whereas it wasn’t until the late 1980s that SSRIs were approved by the FDA as treatments for depression.

• Tricyclic antidepressants are significantly more likely to cause side effects and interact with other medications than SSRIs, SNRIs and other newer antidepressants.

• Tricyclic antidepressants generally aren’t used as a first-line treatment for depression, whereas SSRIs are. Instead, TCAs are generally prescribed if SSRIs or other newer antidepressants aren’t effective at controlling symptoms.

Do Tricyclic Antidepressants Work for Anxiety?

Tricyclic antidepressants typically aren’t prescribed as first-line treatments for anxiety. However, research has found that some TCAs are effective as anxiety medications. Some TCAs may be prescribed on or off-label to treat certain types of anxiety. 

Can Tricyclic Antidepressants Cause Weight Gain?

Yes. Tricyclic antidepressants are commonly associated with weight gain. Several studies have noted that people prescribed TCAs tend to gain a small to moderate amount of weight over the course of treatment.

In a 1984 study, people prescribed low to modest doses of several tricyclic antidepressants had a mean monthly weight gain of 1.3 to 2.9 lbs and an average weight gain of three to 16 lbs over the treatment period.

A study published in 2011 found that patients prescribed nortriptyline, a tricyclic antidepressant, gained an average of 2.64 lbs over 12 weeks -- more than those who were prescribed the SSRI escitalopram.

If you’re prescribed a tricyclic antidepressant and have recently gained weight, it’s important to talk to your healthcare provider before making any changes. 

Your healthcare provider may be able to recommend a different type of antidepressant that has less of an impact on your appetite and/or body weight.

Can You Overdose on Tricyclic Antidepressants?

Yes, you can overdose on tricyclic antidepressants. In fact, overdoses involving TCAs are some of the most common causes of drug poisoning seen in emergency departments.

Overdosing on tricyclic antidepressants can be fatal. If you, your child or a person close to you has either accidentally or intentionally taken an overdose of a TCA or any other antidepressant, call 911 immediately. 

Is It Safe to Stop Taking Tricyclic Antidepressants?

If you’re prescribed a tricyclic antidepressant and want to stop taking it, it’s important to talk to your healthcare provider before doing so.

If you abruptly stop taking a tricyclic antidepressant, you may experience withdrawal symptoms that can have a significant negative impact on your health and quality of life. 

Stopping antidepressants too early may also cause your depression to develop again, affecting your recovery and setting back your progress.

To stop taking a TCA or other antidepressant safely, talk to your healthcare provider first. They may suggest tapering your dosage and/or switching to a long-acting antidepressant during the tapering process to reduce your risk of developing antidepressant discontinuation effects.

Can You Drink Alcohol While Using TCAs?

Drinking alcohol while you’re using antidepressants, including tricyclic antidepressants, is not recommended. Alcohol and antidepressants can both cause drowsiness and make you less alert, increasing your risk of injury.

Alcohol can also contribute to depression and may worsen your symptoms, or lead to suicidal thoughts and actions. The combined effects of alcohol and antidepressants may also increase strain on your liver. 

If you drink alcohol often or have an alcohol use disorder, make sure to talk to your healthcare provider about the safety of drinking during treatment for depression. 

Read our article on alcohol and amitriptyline for more details on this specific TCA and drinking.

TCAs were once cutting edge medications that were widely used to treat depression. However, these days, they’re rarely used except as second-line treatments when SSRIs and other drugs aren’t effective.

If you think you might be depressed and need help working out what type of medication to use, it’s important to talk to a licensed healthcare provider.

Our anxiety medication online service allows you to consult with a licensed psychiatry provider via video chat for an evaluation. You’ll receive private, ongoing follow-ups and, if appropriate, medication to help you control your depression symptoms and work towards recovery.

Interested in learning more about treating depression? Our free mental health resources share techniques that you can use to gain more control over your mental health and deal with issues such as depression, anxiety, stress and more.