How to choose the best antidepressant: what tricyclic antidepressants show about your genes

Doctors can choose from many medications for depression, anxiety and other mental health conditions, including antidepressants, anti-anxiety medications, antipsychotics and mood stabilizers. But one dose does not fit everyone. The same medication at the same dose can help one person, do nothing for another and cause side effects in a third. Genes are one important reason. Tricyclic antidepressants are a clear example of how genetic differences change the right drug and the right dose, and of how a genetic test can help.

Why do people respond differently to the same antidepressant?

Many factors affect how well an antidepressant works, including the type of depression, other health conditions, other medications, alcohol and how regularly the medication is taken. Genes also play a role. Most medications used in psychiatry are broken down by enzymes in the liver, and the genes that make these enzymes vary from person to person:

• Poor metabolizers break some medications down very slowly. Levels can build up and cause side effects.
• Intermediate metabolizers break them down more slowly than usual.
• Normal metabolizers break them down at the expected rate.
• Rapid and ultrarapid metabolizers break them down faster than usual. Levels may stay too low for the medication to work.

These differences are predictable from your DNA, which is why genetic testing can help guide the choice of medication and dose.

What are tricyclic antidepressants?

Tricyclic antidepressants (TCAs) are among the oldest antidepressants. The antidepressant effect of the first one, imipramine, was discovered in the late 1950s. They are named after their chemical structure, which contains three rings of atoms. Examples include:

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

When are tricyclic antidepressants used today?

TCAs work well for depression, but newer antidepressants such as SSRIs and SNRIs are usually tried first because they have fewer side effects and are safer in overdose. The Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 guidelines list TCAs as second-line medications for major depression. CANMAT also notes that TCAs still have an important role when depression has not responded to other treatments:

• Nortriptyline has the fewest side effects among TCAs and is a good option for older adults and after a stroke.
• Amitriptyline can help when depression comes with a painful condition.
• Clomipramine can help when depression comes with obsessive-compulsive disorder.

TCAs are also often prescribed at low doses for conditions other than depression, such as nerve pain and other chronic pain, fibromyalgia, irritable bowel syndrome, migraine prevention and sleep problems.

This makes TCAs especially useful for people who have depression together with one of these conditions. Depression and chronic pain often occur together, and each can make the other worse. A single TCA, such as amitriptyline or nortriptyline, may help both the mood and the pain, and can also improve sleep, which means fewer medications and fewer chances for drug interactions. The same applies to people with depression and migraine, irritable bowel syndrome or insomnia. Because the doses needed for depression are usually higher than those used for pain, knowing how your body breaks down TCAs is especially helpful in these situations. Read more about medications for pain and depression and options for treatment-resistant depression.

What side effects can tricyclic antidepressants cause?

• Anticholinergic effects, such as dry mouth, constipation, blurred vision and trouble urinating.
• Drowsiness, dizziness and a drop in blood pressure when standing up, which can lead to falls.
• Weight gain.
• Effects on the heart rhythm, including a longer QT interval. Your doctor may check an electrocardiogram (ECG) before starting, especially if you are older or have heart disease. Read more about genes and drug-induced heart rhythm problems.

TCAs are also more dangerous than newer antidepressants in overdose, because they can cause confusion, heart toxicity and seizures. Many of these effects are more likely when drug levels are high, which is where genes come in.

How do CYP2D6 and CYP2C19 affect tricyclic antidepressants?

Two liver enzymes do most of the work of breaking down TCAs:

• CYP2D6 breaks down all TCAs. Nortriptyline and desipramine depend mainly on CYP2D6.
• CYP2C19 also breaks down amitriptyline, imipramine, clomipramine, doxepin and trimipramine, turning them into other active forms. For example, CYP2C19 turns amitriptyline into nortriptyline, which CYP2D6 then breaks down.

Differences in these genes are common. Across world populations, between 0.4% and 5.4% of people are CYP2D6 poor metabolizers, and between 1% and 21% are ultrarapid metabolizers, depending on ancestry. Based on these results, the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for TCAs advises, for treating depression:

• CYP2D6 ultrarapid metabolizers: avoid TCAs if possible, because they may not work at usual doses, and consider another medication.
• CYP2D6 poor metabolizers: avoid TCAs if possible because of the risk of side effects. If a TCA is needed, consider a 50% lower starting dose and blood level monitoring.
• CYP2D6 intermediate metabolizers: consider a 25% lower starting dose.
• CYP2C19 rapid and ultrarapid metabolizers: avoid amitriptyline and the other TCAs that depend on CYP2C19, and consider one that does not, such as nortriptyline or desipramine.
• CYP2C19 poor metabolizers: avoid amitriptyline and the other TCAs that depend on CYP2C19 if possible. If one is needed, consider a 50% lower starting dose and blood level monitoring.

For the lower doses of amitriptyline used for nerve pain, CPIC recommends no dose change for poor or intermediate metabolizers, but close monitoring for side effects. CYP2D6 ultrarapid metabolizers may not benefit even for pain, so another medication should be considered. Other medications matter too: some antidepressants, such as fluoxetine, paroxetine and bupropion, strongly block CYP2D6 and can make a normal metabolizer act like a poor metabolizer. A pharmacist can check your genetic results together with all your medications.

How can a Pillcheck test help?

A genetic test does not decide which antidepressant is best by itself. It shows which medications and doses are a better fit for your body, so you and your doctor can avoid some of the trial and error. Your doctor will still consider your symptoms, other conditions, other medications and your preferences.

A Pillcheck test reports CYP2D6, CYP2C19 and other genes that affect TCAs, SSRIs, SNRIs and many other medications. A pharmacist reviews your results together with all your medications, and your report can be shared with your doctor and pharmacist. If antidepressants have not worked for you in the past, your results can help explain why and guide the next choice. Read more about how DNA testing can help find the best anxiety and depression medication and what to do when antidepressants are not working.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge. If you have questions, please contact us.

Summary

• The same antidepressant and dose can work very differently from one person to another, partly because of genes.
• Tricyclic antidepressants are second-line medications for depression and are often used at low doses for pain, migraine and sleep. They can be especially useful for people who have depression together with chronic pain, migraine, irritable bowel syndrome or insomnia.
• TCAs can cause anticholinergic effects, dizziness, weight gain and heart rhythm changes, and are dangerous in overdose.
• CYP2D6 and CYP2C19 break down TCAs. CPIC gives advice to avoid them or change the dose for poor, intermediate, rapid and ultrarapid metabolizers.
• Other medications can block CYP2D6, so a pharmacist should review your genes and medications together.

Frequently asked questions

Are tricyclic antidepressants still prescribed?

Yes. They are usually not the first choice for depression, but they remain useful when other antidepressants have not worked, and at low doses for pain, migraine and sleep.

Does genetic testing matter for low-dose amitriptyline?

It can. CPIC does not recommend changing a low dose for poor or intermediate metabolizers, but they should be watched closely for side effects such as drowsiness, dry mouth and dizziness. CYP2D6 ultrarapid metabolizers may not benefit, so another medication may be a better choice.

Can my genetic results be used for future prescriptions?

Yes. Your genes do not change, so the same results can guide future prescriptions of TCAs and many other medications.

Should I stop my antidepressant if my results show I am a poor metabolizer?

No. Do not stop or change a medication on your own. Share your results with your doctor or pharmacist, who can decide whether any change is needed.

References

Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102(1):37-44.

Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 update on clinical guidelines for management of major depressive disorder in adults. Can J Psychiatry. 2024;69(9):641-687.

Gaedigk A, Sangkuhl K, Whirl-Carrillo M, et al. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 2017;19(1):69-76.

Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes and serotonin reuptake inhibitor antidepressants. Clin Pharmacol Ther. 2023;114(1):51-68.