TCAs (Tricyclic Antidepressants)
What are Tricyclic Antidepressants (aka TCAs)?
They are one of the earlier classes of antidepressants. While they are still used today in select patients, they are not considered first or second line options because they can have slightly more side effects than newer antidepressants.
When were TCAs 1st used to treat depression?
1950s. So they are one of the oldest psychiatric medications classes.
There are many different TCAs and they work in different ways, so how are TCAs categorized?
There are tertiary amines which work on both serotonin and norepinephrine and there are secondary amines, which tend to focus more on norepinephrine.
They are also broken down according to their level of anticholinergic side effects (see below for more on that).
How do tertiary amines compare to secondary amines?
Tertiary amines are older and tend to have more side effects, but they are considered slightly more effective than secondary amines. That said, given the side effect burden, secondary amines are usually tried before tertiary amines.
Compared to modern antidepressants, what are some examples of specific psychiatric conditions that might benefit from TCAs?
-Melancholic depression: depression that involves severe loss of pleasure, high guilt, low appetite, psychomotor slowing, and early morning wakening.
-Depression with Chronic Pain: While the SNRIs such as duloxetine can help with this, studies have shown that amitriptyline may be a nice alternative. https://advancesinrheumatology.biomedcentral.com/articles/10.1186/s42358-020-00137-5
-Depression with Irritable Bowel Syndrome: Amitriptyline and imipramine are more effective than SSRIs in treating IBS. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127815
-Prevention of Depression Relapse after ECT: The gold standard to help slow the relapse to depression after ECT is a combination of Lithium and nortriptyline. https://pubmed.ncbi.nlm.nih.gov/11255384/
-OCD: There is some evidence that Clomipramine may be stronger than SSRIs in treating OCD. https://pubmed.ncbi.nlm.nih.gov/31082050/
Can TCAs be used as add-on treatments for those with depression?
-Yes they can, but with caution because of interactions with the liver that change the breakdown of the medications being used. Nortriptyline is one of the better studied TCAs for this and you can follow its serum levels over time via lab testing.
-Clomipramine is often used on top of SSRIs when treating OCD that hasn’t responded to other, first line treatments.
What are the big side effects to watch for with most TCAs?
-They are much more toxic in overdose than more modern antidepressants so they should be avoided in those who have multiple previous and recent suicide attempts.
-They can cause cardiac conduction changes, or arrhythmias so watch in those with cardiac histories.
-Sedation: we sometimes use this to our advantage to help with sleep, such as with doxepin (sinequan) and amitritiptyline
-Weight gain: some more than others
-Sexual dysfunction such as lower sex drive or harder to achieve orgasm (this means these are sometimes used to treat premature ejaculation).
-Anticholinergic side effects: including constipation, urinary retention, dry mouth, blurred vision, and in the elderly, confusion.
-Orthostatic falls, especially in the elderly.
-Liver toxicity: very rare, at about 4/100,000
What are the ways to manage the various anticholinergic side effects?
-1st off, the level of anticholinergic side effects is much less in desipramine & nortriptyline.
-Amitriptyline is most anticholingeric of all the TCAs
-Constipation: use docusate 100mg BID with sennosides 8.6mg intermittently as needed; Bethanechol 10-25mg TID in severe cases.
-Dry mouth can lead to cavities: use Xylitol gum TID; can also use Biotin products. Some also use Pilocarpine 4% rinse (do not swallow).
-Orthostasis: can lead to falls and even fainting. If this occurs you can try a high salt diet but if it’s bad enough a change of medicine is necessary.
-Urinary retention: Bethanechol 25mg TID
Which TCA is best for OCD?
Clomipramine 25mg to 250mg/day because its the most seritonergic of the TCAs.
Which TCA is best for insomnia?
-Doxepin 3-6mg
-Amitriptyline 25mg (but is most anticholinergic of all TCAs)
Which TCA is best for ADHD?
-Desipramine because it has the highest NE activity and is the least sedation (it actually can be activating).
Which are the Tertiary Amine TCAs (meaning they work on norepinephrine AND serotonin), and what is their dosing range?
-Amitriptyline: also very sedating so used for insomnia. Great for headaches, IBS, and chronic pain. Highly anticholinergic. Start 25-50mg. Target 150-300mg/day.
-Clomipramine: Best for OCD because it’s highly serotonergic. Start 25mg/day; target 150-250mg/day.
-Doxepin: most sedating and antihistaminergic. Only use 3-6mg for insomnia. For Depression start 25-75mg/day and target 150-300mg/day.
-Imipramine: Best for anxiety and panic. Start 25-50mg/day; target 150-300mg/day.
Which are the Secondary Amine TCAs (target norepinephrine more)?
-Desipramine: Most activating/least sedating and actually used for adult ADHD. Least anticholinergic too. Start 25-50mg/day; target 75-300mg/day.
-Nortriptyline: Lowest risk of orthostasis and weight gain. Great for post-ECT use to prevent depression (along with Lithium). Start 25-50mg/day; target 50-150mg/day.
Which TCAs are the ones to get serum levels on?
Get levels 12 hours after the last dose and at least 5-6 days after changing he dose.
-Only 3 are accurate and should be followed: Nortriptyline, Imipramine (its metabolite is Desipramine), and Desipramine.
-Nortriptyline: U-shaped curve so its least effective at a level below 50 and above 150 ng/ml
-Imipramine: the best level is > 200 ng/ml (and this includes its active metabolite desipramine)…but avoid levels > 250 ng/ml because side effects increase.
-Desipramine: Goal is a level > 125 ng/ml
Can genetic testing be helpful when prescribing TCAs?
It is not mandatory but it is helpful to know how active the patient’s 2D6 enzymes are. If they are slow metabolizers there then we should go up more quickly and lower the maximum dose for amitriptyline & clomipramine by 50%.
