Learn about the differences between tricyclic antidepressants and SSRIs, including side effects, drug interactions, efficacy and safety.

Depression is a mental health condition that many people experience. It can cause feelings of sadness or emptiness and people struggling with depression may feel like they have nothing to live for. It can also be debilitating and very serious. Treating depression properly with counseling or medication can help people recover.

There are several types of antidepressant medicationsTricyclic antidepressants are older drugs, in use since the late 1950s. Selective serotonin reuptake inhibitors (SSRIs) are newer and have been in use since the late 1980s. Although these classes of drugs have some similarities, there are many key differences to be aware of.

Article at a Glance:

Keep the following key points in mind when considering tricyclic antidepressants vs. SSRIs:

  • Both classes of drugs help depression by influencing the amounts of serotonin and norepinephrine in the brain.
  • Both classes of drugs are associated with various side effects and can interact with each other, with alcohol and with other drugs.
  • A rare, serious syndrome called serotonin syndrome can occur with SSRI or tricyclic antidepressant use.
  • Tricyclic antidepressants are less selective than SSRIs, meaning they have the potential to affect more body systems. They also have more potential for serious or fatal toxicity when taken in large amounts, compared with SSRIs.
  • SSRIs are generally safer than tricyclic antidepressants with regard to cardiovascular risks.

Differences in the Efficacy

Before discussing how well these antidepressant medications work, it’s important to understand what brain chemicals they work on. Serotonin is a chemical that is thought to enhance mood. In theory, mood improves as more serotonin is available within the brain. Norepinephrine is another brain chemical that has an effect on mood. Importantly, both of these substances have many other functions throughout the body. Tricyclic antidepressants and SSRIs have been used to treat depression effectively. There doesn’t appear to be a difference in how effective they are.

Tricyclic antidepressants work by inhibiting certain transporters in the brain that carry serotonin and norepinephrine into neurons. This transition causes more of those chemicals to be available for other neurons to use and is thought to be the mechanism for improving symptoms of depression. Although tricyclic antidepressants can be effective, many people do not tolerate them because of their side effects. These drugs act on many other receptors throughout the body, meaning they are not selective, and this is the reason for most of the side effects. Tricyclic antidepressants usually have more of an effect on norepinephrine levels than on serotonin levels.

SSRIs also cause more serotonin to be available for neurons to use, by selectively inhibiting serotonin transporters. SSRIs can also cause more norepinephrine to be available, but usually less than what tricyclic antidepressants do. They are different from tricyclic antidepressants because they are much more selective as to which receptors they work on throughout the body, so they usually have fewer side effects.

Tricyclic antidepressants may work better than SSRIs in people with severe depression and in those who are being treated as inpatients.

Differences in the Side Effects

Since tricyclic antidepressants are very non-selective, meaning that they have effects on many receptors throughout the body, their use is associated with several side effects. Sometimes these side effects can be serious. SSRIs are more selective for serotonin transporters. While they are usually associated with fewer side effects, SSRIs can still cause adverse effects. Usually, SSRIs are much easier to tolerate than tricyclic antidepressants since the side effect profile is better for most people.

Side effects more common in tricyclic antidepressants:

Although the following side effects can occur with both tricyclic antidepressants and SSRIs, they are more common with tricyclic antidepressants:

  • Dry mouth
  • Sleepiness
  • Blurry vision
  • Constipation
  • Weight gain
  • Difficulty urinating

Side effects more common in SSRIs:

Certain side effects appear to be more common with SSRI use compared with tricyclic antidepressants use, although they can occur with both types of medications, including the following:

  • Nausea
  • Sexual difficulty
  • Headache
  • Insomnia
  • Agitation
  • Gastrointestinal problems

Tricyclic antidepressants and SSRIs can be associated with cardiovascular problems, but tricyclics have a much higher rate of these serious side effects. Tricyclic antidepressant use has been associated with stroke, heart rhythm disturbances, low blood pressure and sometimes heart failure.

Differences in Toxicity & Safety

Tricyclic antidepressants can be much more dangerous than SSRIs in overdose situations, since they act on more receptors throughout the body, especially within the cardiovascular system and the nervous system. Generally, it takes larger amounts of an SSRI than a tricyclic to cause serious toxic effects. Tricyclic antidepressants can cause fatal toxicity with overdose since they directly affect the function of the heart. SSRIs have much less effect on the cardiovascular system. Although overdoses of SSRIs can still cause serious problems, they are generally safer than tricyclic antidepressants in this regard.

A serious — but uncommon — syndrome called serotonin syndrome can occur with the use of drugs that increase serotonin levels, including both SSRIs and tricyclic antidepressants. Serotonin syndrome can be fatal if not treated quickly. Symptoms of serotonin syndrome include muscle twitching, confusion, fever, seizures and heart problems.

Tricyclic antidepressants and SSRIs are safe for most people when used as prescribed and under the supervision of a medical professional, but SSRIs generally have an improved safety profile compared with tricyclic antidepressants.

Possible Drug Interactions

Tricyclic antidepressants have more potential to be associated with drug interactions than SSRIs due to their non-selective actions throughout the body. Tricyclic antidepressants can interact with several medications, including:

  • Diuretics (drugs that increase urination)
  • Blood pressure medications
  • Other drugs that affect the heart

Drug interactions with tricyclic antidepressants and SSRIs can also result in serotonin syndrome when more than one medication that affects the serotonin system is being given. Many other drugs can increase serotonin levels, even if they are not being used to treat depression. It’s important to note that drug interactions can potentially occur with any medication and to inform your healthcare provider of all medications that you are taking.

Mixing with Alcohol

One side effect of tricyclic antidepressants is nervous system depression and sedation. Since alcohol also depresses the nervous system, using both substances at the same time can result in major sedation or drowsiness. The use of alcohol concomitantly with tricyclic antidepressants can also increase the risk of toxicity of the antidepressant. It is generally not recommended to use alcohol while taking SSRIs or tricyclic antidepressants.

SSRIs and tricyclic antidepressants are generally safe and effective when used as indicated and under the supervision of a healthcare provider. Always tell your medical provider about all the medications you are taking.

Related Topic: SSRI vs SNRI

Thomas Christiansen
Editor – Thomas Christiansen
With over a decade of content experience, Tom produces and edits research articles, news and blog posts produced for Advanced Recovery Systems. Read more
Christina Caplinger
Medically Reviewed By – Christina Caplinger, RPh
Christina Caplinger is a licensed pharmacist in both Colorado and Idaho and is also a board-certified pharmacotherapy specialist. Read more

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Bartlett, D.; et al. “Drug-Induced Serotonin Syndrome.” February 2017. Accessed August 31, 2019.

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Medical Disclaimer

The Recovery Village aims to improve the quality of life for people struggling with substance use or mental health disorder with fact-based content about the nature of behavioral health conditions, treatment options and their related outcomes. We publish material that is researched, cited, edited and reviewed by licensed medical professionals. The information we provide is not intended to be a substitute for professional medical advice, diagnosis or treatment. It should not be used in place of the advice of your physician or other qualified healthcare providers.