Tricyclic Antidepressant Clinical Pearls

Tricyclic antidepressants are still used in clinical practice. Their use has diminished over time as newer and generally safer medications have been invented, but you will see them occasionally. In my primarily geriatric practice, I would say that I see them a couple of times per week. I will outline some of the most important tricyclic antidepressant clinical pearls.


Tricyclic antidepressants have a wide variety of indications. As implied by the name, they can be used for depressive disorders. They inhibit the reuptake of serotonin as part of their mechanism of action so one can understand why they might be useful for this. Another part of their mechanism is that they can inhibit the reuptake of norepinephrine as well. If you understand pharmacology, you can surmise that this may provide some benefit in various pain syndromes. Indeed this is true as you may see these drugs used in conditions like fibromyalgia and possibly neuropathic pain syndromes.

In addition to the depression and pain benefit, there are a few oddball indications where a TCA may be indicated. The most common that I have seen in practice is headache prophylaxis, excessive salivation, and sleep disorders.

Anticholinergic Activity

To understand why this class of medications isn’t used very often, you have to go no further than recognizing that these drugs are highly anticholinergic. This means that for anyone over the age of 60ish, you’ll likely want to do the best you can to find other alternatives. Constipation, dry eyes, confusion, dry mouth, and urinary retention are common. Here’s a list of how those adverse effects can contribute to the prescribing cascade. I talk about this problem extensively in my latest book Perils of Polypharmacy.


Sedation is a very important adverse effect that can be a potential benefit in some situations. In a patient with fibromyalgia that has a lot of trouble with insomnia, a TCA with sedative properties might help with both symptoms. One should be advised that if a patient reports hypersomnolence associated with certain conditions, a TCA would be a poor selection.

Of the TCAs, doxepin may tend to be the most sedating. It is also an agent that I have seen used for refractory itching cases. This makes sense because doxepin is purported to be one of the more potent agents when it acts on histamine-1 (H1) receptors.

Drug Interactions

Drug interactions can be problematic with the TCAs. In a classic previous post, I discuss how CYP2D6 could cause some problems with a certain TCA. In addition to some CYP enzyme interactions, you must remember to look for anticholinergic burden. Using a TCA on top of other medications that carry anticholinergic activity is far from ideal and will likely lead you down the path of one or more anticholinergic adverse effects which can easily lead to polypharmacy. If you’d like to learn more about some of the most critical drug interactions in clinical practice, take advantage of Audible’s free book promotion. You can have my book on drug interactions for free if you have never tried Audible before; just follow this link and sign up. There is no required commitment to continue with an Audible membership and many have used this to obtain 8 hours of free medication education.

Drug Levels

While most tricyclic antidepressants are dosed based upon clinical response and the risk for adverse effects, uniquely, nortriptyline has drug levels that we can monitor. Target levels between 50-150 ng/mL.


Cardiac complications can result from the overdose of tricyclic antidepressants. This, along with their anticholinergic potential is the reason why they have fallen out of favor in the management of depression compared to newer, generally safer antidepressants like the SSRIs. In patients with preexisting cardiovascular issues, TCAs may be an even higher risk selection.


Another concern that I have seen with TCAs is orthostasis. This is most prominent as patients age and the risk of falls can rise. Monitoring blood pressure, reducing doses, and avoiding TCAs in a frequent faller is important to consider in a patient with dizziness, falls, and/or low blood pressure.

So that about wraps up my important tricyclic antidepressant clinical pearls. Please leave a comment below if you have something to add or if you have seen something specific in your clinical practice!

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1 Comment

  1. Jim Smith

    Nortriptylibe works backward on me. Every time I try to reduce dosage I get severe abdominal pain. Been 9 months and still on 7 mg. No one knows why.


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Written By Eric Christianson

December 22, 2021

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