If you’ve been prescribed a tricyclic antidepressant (TCA), or you’re considering one because other depression treatments haven’t worked, you probably have questions about what these medications do and how effective they are. And if you’ve been prescribed one for nerve pain, migraines, or sleep problems, you might be wondering why you’ve been given an antidepressant at all.
Tricyclic antidepressants work primarily by increasing the availability of two chemical messengers in the brain: serotonin and norepinephrine. These neurotransmitters play a role in mood, but also in sleep and how the body processes pain – which helps explain why TCAs are prescribed for more than just depression.
In this guide, we’ll explain how TCAs work, what they’re used for, their potential side effects, and how they compare with newer antidepressants. We’ll also explore the treatment options available if antidepressants haven’t worked for you.
What are tricyclic antidepressants?
Tricyclic antidepressants are one of the oldest classes of antidepressant medication. They were first introduced in the 1950s and get their name from their chemical structure, which contains three connected rings.
TCAs were once a standard first-line treatment for depression. Today, newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are generally tried first because they tend to cause fewer side effects and are safer in overdose.
That doesn’t mean tricyclic antidepressants don’t work or can’t be used safely. They remain an effective treatment option for many people with depression, particularly when other medications haven’t provided enough relief or haven’t been well tolerated. Their effects on pain, sleep, and other functions also mean that some TCAs are now frequently prescribed for reasons unrelated to depression.
What are tricyclic antidepressants used for and which medications are TCAs?
Depression remains one use for tricyclic antidepressants, particularly when other antidepressants (like SSRIs) haven’t helped sufficiently.
However, depending on the specific medication, TCAs are also now widely used for conditions other than depression, including nerve or chronic pain, migraine prevention, insomnia, and obsessive-compulsive disorder (OCD).
Some commonly prescribed tricyclic antidepressants and examples of how they are used include:
| Medication | Examples of uses |
| Amitriptyline | Depression; also commonly used for nerve pain and migraine prevention |
| Nortriptyline | Depression; also used for certain types of nerve pain |
| Imipramine | Depression; also used for childhood bedwetting |
| Desipramine | Depression |
| Doxepin | Depression and anxiety; certain formulations are also used for insomnia |
| Clomipramine | Obsessive-compulsive disorder (OCD) |
It’s worth noting that not all of these uses are FDA-approved. Some are off-label uses, which simply means a medication is being prescribed for a condition other than the one it was originally approved to treat. Off-label prescribing is a common and established part of medical practice, and prescribers use their clinical judgment.
So, if you’ve been prescribed a TCA for pain, migraines, or sleep, this doesn’t mean your provider believes you have depression. The same medication can have different therapeutic effects for other symptoms, often at different or lower doses.
How do tricyclic antidepressants work?
Brain cells communicate using chemical messengers called neurotransmitters. After neurotransmitters have carried a message between cells, some are normally reabsorbed by the cell that released them – a process known as reuptake.
Tricyclic antidepressants primarily block the reuptake of serotonin and norepinephrine, leaving more of these neurotransmitters available between nerve cells.
What that means in practice depends partly on why you’re taking them.
For depression, changing serotonin and norepinephrine signaling can help improve mood and other symptoms over time. For some types of chronic or nerve pain, these same neurotransmitters are involved in pathways that regulate pain signals, which can help reduce how strongly pain is experienced. Some TCAs also have sedating effects, which is one reason certain medications may be used for sleep problems.
TCAs also interact with several other chemical signaling systems. These additional effects can sometimes contribute to their therapeutic uses, but they’re also responsible for many of their side effects.
Of course, this is a simplified explanation of how TCAs work. Their effects on depression, pain, and other conditions involve complex processes that aren’t yet fully understood. In depression particularly, increasing serotonin and norepinephrine is only part of the picture: depression isn’t simply caused by having too little of these chemicals, and antidepressants don’t simply correct a “chemical imbalance.”
What are the side effects of tricyclic antidepressants?
Because TCAs affect several different chemical signaling systems, they can cause a wider range of side effects than many newer antidepressants. Some of the most common include:
| What else TCAs can affect | Possible side effects |
| Acetylcholine signaling | Dry mouth, constipation, blurred vision, difficulty urinating |
| Histamine signaling | Drowsiness, increased appetite or weight gain |
| Blood pressure regulation | Dizziness or lightheadedness, particularly when standing |
Other possible side effects can include sweating, changes in heart rate, or sexual side effects. However, it’s important to remember that not everyone experiences these side effects, and the type and severity can vary between individual TCAs and from person to person. Some may also improve as your body adjusts.
If side effects are troublesome or you develop new symptoms after starting medication, speak to your prescriber. They can determine whether your symptoms are expected, whether your medication or dose needs adjusting, or whether another treatment might suit you better. Get urgent medical help (call 911) if you have chest pain, a racing or irregular heartbeat, fainting, or a seizure.
SSRIs vs. tricyclics: what’s the difference?
SSRIs and tricyclic antidepressants can both be effective treatments for depression, and research comparing the two has not found a significant overall difference in how effectively they treat depressive symptoms. The bigger differences are in how they work, their side effects, and how they’re typically used today.
SSRIs primarily increase the availability of serotonin. Tricyclics affect both serotonin and norepinephrine and interact with several other signaling systems.
SSRIs have largely overtaken TCAs as the first-line medication choice for depression because they tend to be better tolerated and are safer in overdose – not because tricyclic antidepressants don’t work. SSRIs can cause side effects too, such as nausea or sexual side effects, but people are generally less likely to stop taking them because of side effects.
TCAs also have established uses beyond depression, particularly for conditions such as neuropathic pain, whereas SSRIs don’t generally have the same role in pain management.
However, for some people, a TCA may provide relief when newer antidepressants haven’t. The most appropriate medication ultimately depends on your symptoms, medical history, and individual response to treatment.
Are tricyclic antidepressants safe?
When prescribed and monitored properly, TCAs are used safely by many people. They do require some additional care compared with many newer antidepressants, however, and there are a few important things to know.
Your prescriber needs to know about any other medications or supplements you take and any health conditions you have, particularly certain heart conditions, as TCAs can affect heart rhythm. TCAs can also cause drowsiness and dizziness, and alcohol may make these effects stronger. Ask your healthcare provider about drinking alcohol with the specific medication you’ve been prescribed.
It’s also important not to stop taking a TCA suddenly unless you’ve been advised to do so. Your prescriber can help you reduce your dose gradually if you need to stop treatment.
One important difference between TCAs and many newer antidepressants is that taking too much can be particularly dangerous. An overdose can affect the heart and nervous system and can be life-threatening.
If you think you or someone else may have taken too many tricyclic antidepressants, call 911 for an emergency or Poison Control at 1-800-222-1222 for immediate guidance.
Don’t wait for symptoms to develop. If you’re experiencing suicidal thoughts or a mental health crisis, call or text 988 to reach the Suicide & Crisis Lifeline.
What if antidepressants haven’t worked for you?
If you’re taking a tricyclic antidepressant for depression, there’s a reasonable chance you’ve already tried another antidepressant first.
Finding the right treatment can take some adjustment. If a medication hasn’t provided enough relief, your psychiatric provider may look at whether you’ve taken an appropriate dose for long enough, whether side effects are affecting treatment, and whether adjusting the dose, switching medication, combining treatments, or adding therapy could help.
If you’ve tried multiple antidepressants without adequate improvement, your provider may also assess whether you have treatment-resistant depression (TRD). Despite the name, treatment-resistant doesn’t mean untreatable. There are other treatment approaches available beyond simply trying another traditional antidepressant.
One option is Spravato (esketamine), a nasal spray that works differently from traditional antidepressant medications.
How is Spravato different from traditional antidepressants?
Unlike tricyclic antidepressants, SSRIs, and many other traditional antidepressants, Spravato doesn’t primarily work through serotonin or norepinephrine. Instead, it acts on a different signaling system involving glutamate, through NMDA receptors.
Spravato® (esketamine) is FDA-approved for adults with treatment-resistant depression who have not responded adequately to at least two oral antidepressants. It can be prescribed either on its own or alongside an oral antidepressant, and is administered as a nasal spray in a certified healthcare setting, where patients are monitored after each treatment.
Spravato isn’t the right treatment for everyone, and experiencing limited benefit from one antidepressant doesn’t automatically mean you have treatment-resistant depression. A psychiatric evaluation can look at your full treatment history and help determine what options are appropriate for you.
Finding the right treatment at REACH Behavioral Health
There’s no single medication or treatment that’s right for everyone with depression. The important thing is having a treatment plan that takes into account your symptoms, previous experiences, response to medication, side effects, and wider mental health needs.
At REACH Behavioral Health, our psychiatric team offers comprehensive psychiatric evaluation and medication management, helping you understand your options and adjust treatment when something isn’t working as it should.
Therapy and counseling are also important parts of treatment for depression, while eligible adults with treatment-resistant depression may also benefit from access to Spravato treatment.
At REACH, we also provide treatment and support for a wider range of behavioral and mental health concerns, including anxiety, OCD, and insomnia. So, whether you’re struggling with depression, have questions about your current antidepressant medication, or need support with another mental health concern, we can help you explore the treatment options available.
You can meet with us online or in person, no referral is needed, and we accept most major insurance plans.
Book a psychiatry appointment with REACH Behavioral Health today to discuss your treatment options and next steps.
FAQs about tricyclic antidepressants
What are tricyclic antidepressants usually used for?
Tricyclic antidepressants were originally developed to treat depression and are still used for this today, particularly when other antidepressants haven’t provided enough relief. However, certain TCAs are also commonly prescribed for other conditions, including nerve pain, migraine prevention, and insomnia, sometimes as an off-label treatment.
Is trazodone a tricyclic antidepressant?
No. Trazodone is an antidepressant, but it isn’t a tricyclic antidepressant. It belongs to a different class of medication and affects serotonin differently. Trazodone is approved to treat depression and is also commonly prescribed off-label for insomnia.
What is the most commonly used tricyclic antidepressant?
Amitriptyline is one of the most commonly prescribed tricyclic antidepressants in the US. Today, it is frequently prescribed for conditions such as nerve pain and migraine prevention as well as depression.
How long do tricyclic antidepressants take to work?
It depends partly on why you’re taking one. For depression, improvement typically begins after around two to four weeks, and the full benefit can take longer. For pain, relief generally builds over several weeks. Some effects, such as drowsiness, can appear much sooner. Your prescriber can tell you when they expect to assess your response based on your medication and the condition being treated.
Can you drink alcohol while taking a tricyclic antidepressant?
It’s generally best to avoid or limit alcohol. Alcohol can increase side effects such as drowsiness and dizziness when combined with tricyclic antidepressants, and it can also worsen low mood. Ask your prescriber or pharmacist what’s safe for you with the specific TCA you’re taking. If cutting down feels difficult, support is available, including alcohol counseling at REACH.
Do tricyclic antidepressants work for nerve pain?
For some people, yes. TCAs such as amitriptyline and nortriptyline are commonly used for nerve (neuropathic) pain, and their effect on pain appears to be separate from their effect on mood. Doses can be lower than those used for depression, and they don’t help everyone. Using a TCA for nerve pain is an off-label use, so it’s usually managed by whoever is treating your pain, such as your primary care provider or a pain or nerve specialist.