What are Tricyclic Antidepressants (TCAs) and When are They Prescribed?

Key Takeaways

• Tricyclic antidepressants (TCAs) are among the oldest depression treatments still in use today, with a long history of effectiveness in managing depressive symptoms and certain other mental health conditions
• They carry more side effects and safety risks compared to newer antidepressant options, including potential heart problems, drowsiness, and dangerous interactions with other medications
• TCAs are usually prescribed when other treatments haven't worked or for specific conditions where they may be particularly effective

A woman sits across from her psychiatry provider, frustrated. She's been on three different antidepressants over two years. None of them worked for her depression. Her healthcare professional pulls out a prescription pad and writes down a name she's never heard of. It's a tricyclic antidepressant (TCA) from the 1950s.

TCAs don't get the same attention as Prozac or Zoloft, but they've helped people with depression for over half a century. TCA medication works on multiple brain chemicals at once, which is why it can succeed where newer drugs fail. However, side effects hit harder, and the drugs are dangerous in overdose.

Healthcare professionals prescribe TCAs after other treatments don't work or when someone has both depression and chronic pain. Many people cycle through medications before finding one that helps. For them, an older drug might break through the stress and symptoms.

What are Tricyclic Antidepressants (TCAs)?

Tricyclic antidepressants are a class of older psychiatric medications that treat depression by increasing levels of serotonin and norepinephrine in the brain. According to the National Institutes of Health, tricyclic antidepressants were first introduced in the 1950s. They’re named for their three-ring chemical structure, not for how they affect mood.

These medications ease depressive symptoms by altering how the brain regulates certain neurotransmitters, which led to their widespread use for decades.

With the availability of newer antidepressants, TCAs were prescribed less often, since they carry a higher risk of side effects and require closer monitoring. Today, TCAs are generally considered second- or third-line options rather than first-line treatments.

Even so, they remain relevant when depression doesn't respond to other medications or when mental health symptoms overlap with chronic pain, where their broader effects can still be beneficial.

Common tricyclic antidepressants include:

• Amitriptyline
• Nortriptyline
• Imipramine
• Desipramine
• Clomipramine
• Doxepin
  

Each TCA antidepressant has a slightly different balance of benefits and side effects, so careful selection is important.

How Do TCAs Work in the Brain?

Tricyclic antidepressants block the reabsorption of serotonin and norepinephrine in the brain, keeping these mood-regulating chemicals circulating longer. When these neurotransmitters remain active, many people experience gradual improvements in their depression symptoms over several weeks.

TCAs don't create new chemicals, but they help the brain make better use of what’s already there. TCAs interact with multiple brain receptors beyond those that regulate mood, affecting sleep, alertness, and pain perception.

This wide-reaching activity makes them useful for complicated cases or chronic conditions. It also explains why they cause more side effects like drowsiness, dry mouth, and constipation than newer antidepressants that target specific brain chemicals.

What are the FDA-Approved and Off-Label Uses of TCAs?

TCAs are FDA-approved primarily for depression, but healthcare professionals also prescribe them off-label for conditions like chronic pain, migraine prevention, anxiety disorders, and insomnia.

Mental health and physical pain often feed into each other. Persistent anxiety can trigger headaches, muscle tension, or digestive issues, while chronic pain can deepen depression, disrupt sleep, and increase irritability.

TCAs influence brain chemicals that regulate both mood and pain signals, making them a practical choice when someone experiences depression alongside chronic physical discomfort. Treating both dimensions at once can provide better relief than addressing emotional or physical symptoms separately.

Treating major depressive disorder and anxiety

TCAs are approved to treat major depressive disorder and are sometimes used for anxiety-related symptoms when other antidepressants haven’t helped. They’re most often considered when depression is severe or treatment-resistant.

Treating chronic pain syndromes

Many TCAs are prescribed off-label for chronic pain conditions, including neuropathic pain, fibromyalgia, and migraine prevention. Lower doses are often effective for pain, even when they wouldn’t be enough to treat depression.

Treating obsessive-compulsive disorder

Clomipramine was one of the first proven treatments for obsessive-compulsive disorder because it strongly targets serotonin, a brain chemical closely linked to obsessive thoughts and compulsive behaviors.

By increasing serotonin activity, clomipramine helped reduce the intensity and frequency of intrusive thoughts that drive compulsions. This made it a breakthrough treatment at the time. For many years, it was considered a primary medication option for OCD.

As newer medications became available, selective serotonin reuptake inhibitors (SSRIs)  began to replace clomipramine as first-line treatments. SSRIs target serotonin more selectively, which means they tend to cause fewer side effects and are safer for long-term use.

While clomipramine remains an option when other treatments fail, SSRIs have largely replaced it as the preferred choice due to their milder side effect profile.

"TCAs can still be great options for clients who have not responded well to SSRIs or SNRIs, or are struggling with multiple other symptoms. Some other symptoms that may benefit from TCAs are headaches, migraines, and GI concerns, especially irritable bowel syndrome. Some of the TCAs can also be helpful for sleep if the client has failed other sleep medications."

- Svetlana Stuck, PA-C

What are the Common Side Effects of TCAs and How are They Managed?

Side effects from TCA medication are common, especially when treatment begins or doses increase. Understanding why they happen can make them easier to manage.

Here are some of the common side effects:

Anticholinergic effects

Dry mouth, constipation, blurred vision, and urinary retention can occur since TCAs block acetylcholine. Staying hydrated or adjusting dosage timing can help.

Adrenergic effects

Orthostatic hypotension, which is a drop in blood pressure when standing, is one of the side effects of TCAs. They may also cause dizziness or lightheadedness. Slow position changes and careful dose adjustments can reduce the risk of these side effects.

Histaminic effects

TCAs that block histamine receptors can cause drowsiness and increased appetite, potentially leading to weight gain. Taking the medication at night and regular monitoring with a healthcare professional can help manage these effects.

"Minimizing the needed dose of the TCA can help with minimizing side effects. This may mean using the medication as part of a regimen sometimes. However, the risk for serotonin syndrome has to be monitored closely if multiple serotonergic medications are used. Taking the medication at bedtime can also help with the drowsing effect of some of the TCAs."  

- Talkspace psychiatric provider Svetlana Stuck, PA-C

What are the Serious Risks, Contraindications, and Precautions for TCAs?

Tricyclic antidepressants carry higher risks than many newer medications. Therefore, providers approach them thoughtfully and with close follow-up.

Before prescribing a TCA, a psychiatric provider reviews medical history, symptoms, and other medications to assess whether this option is appropriate. Ongoing check-ins allow monitoring over time, especially during dose adjustments.

Risk of overdose and cardiotoxicity

Tricyclic antidepressants can interfere with the electrical signals that help the heart keep a steady rhythm. In some people, these medications can cause the heart to beat irregularly. This kind of disruption can quickly become dangerous and requires immediate medical attention.

Because of this risk, providers are especially cautious when prescribing TCAs. A history of heart problems or certain medical conditions can make these medications unsafe. Careful dosing and regular monitoring help catch warning signs early and reduce the risk of serious complications.

Serotonin syndrome

Serotonin syndrome is a potentially life-threatening condition that occurs when serotonin levels in the body become dangerously elevated, typically due to medication interactions or excessive doses of serotonin-affecting drugs.

Serotonin syndrome causes symptoms like confusion, agitation, fever, sweating, muscle rigidity, and rapid heartbeat that often develop suddenly. The condition can escalate quickly and requires immediate medical attention.

The risk increases when TCAs are combined with other medications that also raise serotonin, including some antidepressants, certain migraine treatments, and a few pain or herbal products.

Contraindications

TCAs are generally avoided in people with certain cardiac or eye-related conditions. Before starting treatment, the prescriber should carefully review a person’s medical history to assess safety.

What are the Important Drug and Food Interactions with TCAs?

TCAs interact with a class of antidepressants called monoamine oxidase inhibitors (MAOIs), other antidepressants, certain heart medications, alcohol, cold and allergy medications, and some supplements, potentially causing heart rhythm changes, excessive sedation, or dangerously high serotonin levels.

People with heart problems, frequent dizziness or fainting, or those taking multiple medications that affect heart rhythm or alertness may not be good candidates for TCAs. Providing your healthcare professional with a complete list of all prescriptions, over-the-counter drugs, and supplements helps identify potential risks and ensures safer treatment decisions.

Initial dosing and slow titration

TCAs are usually started at a low dose and increased gradually to minimize side effects. This approach allows the body to adjust to the medication while helping healthcare professionals identify the lowest effective dose for each person.

Monitoring requirements

Some individuals need extra monitoring while taking a tricyclic antidepressant because these medications can affect heart rhythm and medication levels in the body. Providers may use an electrocardiogram to assess heart function before starting treatment or after dose changes, especially in individuals with a history of heart concerns.

Blood-level monitoring can also help ensure the dose stays within a safe range, since small increases can sometimes lead to stronger effects or side effects.

Regular monitoring helps providers adjust treatment early and reduce risk, particularly when higher doses or other medical conditions are involved.

Switching between antidepressants

Switching from one antidepressant to another requires careful timing to avoid dangerous interactions or withdrawal symptoms. When transitioning to or from a TCA, healthcare professionals often implement a washout period where the first medication is tapered down and cleared from the body before starting the new one.

The length of this washout period varies depending on which medications are involved, with some combinations like MAOIs and TCAs requiring several weeks between them. Abrupt switches without proper washout periods can lead to serotonin syndrome or other serious complications, making medical supervision essential during any antidepressant transition.

TCAs vs. Newer Antidepressants

Tricyclic antidepressants were the standard treatment for depression for decades, and they remain highly effective for many people. The key question today isn't whether TCAs work, but how their benefits and risks compare to newer antidepressants that have become the preferred first-line treatment.

The table below breaks down the primary differences between these two classes of medications:

Getting Professional Guidance on TCA Treatment

Deciding whether tricyclic antidepressants are appropriate requires professional guidance. A licensed mental health provider can evaluate symptoms, review treatment history, assess potential risks, and determine whether a TCA is the right fit.

Finding the right provider doesn't always require an in-person visit. Talkspace connects individuals with licensed psychiatric providers through a secure virtual platform. These providers can assess whether medication is appropriate, prescribe medications when needed, monitor side effects, and offer ongoing support throughout treatment. Start your journey to better mental health with Talkspace today.

Frequently Asked Questions

Are TCAs addictive?

Tricyclic antidepressants are not considered addictive, but stopping them abruptly can trigger uncomfortable withdrawal symptoms like nausea, headaches, fatigue, and mood changes. Healthcare providers recommend tapering off gradually by reducing the dose in small increments over weeks or months, allowing the body to adjust without sudden chemical shifts.

How long do tricyclic antidepressants take to work?

Most people notice some improvement in their symptoms within two to four weeks of starting treatment. However, it may take six to eight weeks to experience the full therapeutic effects of the medication.

Are TCAs used for anxiety?

Yes, tricyclic antidepressants are sometimes prescribed for anxiety, particularly when it occurs alongside depression. They can be especially helpful for people who haven't responded well to first-line anxiety medications like SSRIs.

Which TCA has the fewest side effects?

Secondary amine TCAs such as nortriptyline and desipramine tend to cause fewer side effects than other tricyclics. These medications are less likely to produce intense sedation or anticholinergic effects such as dry mouth, constipation, and dizziness compared to tertiary amine TCAs like amitriptyline.

Sources:

1. Moraczewski, J, Awosika, AO, Aedma, KK. Tricyclic antidepressants. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK557791/. Accessed August 17, 2023.‍
   

‍Talkspace articles are written by experienced mental health-wellness contributors; they are grounded in scientific research and evidence-based practices. Articles are extensively reviewed by our team of clinical experts (therapists and psychiatrists of various specialties) to ensure content is accurate and on par with current industry standards.

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