Do antidepressants increase the risk of dementia in older adults?

What if you or one of your parents develops depression later in life, and the doctor prescribes an antidepressant? Treating depression is important: untreated depression affects quality of life, physical health and memory. But it also helps to understand the risks of medications and take careful steps to minimize them, especially when other medications are being taken as well.

As we get older, managing medications becomes trickier. The body processes drugs more slowly, and many older adults take several medications for conditions such as high blood pressure, high cholesterol, diabetes and chronic pain, which can interact. A person's DNA also plays an important role. This article explains what research shows about antidepressants and dementia, and how pharmacogenetic testing combined with a pharmacist's medication review can help older adults use antidepressants more safely.

Is there a link between antidepressants and dementia?

Several large studies have found that older adults who take antidepressants are more likely to be diagnosed with dementia later. In an Israeli study of more than 71,000 adults aged 60 and older, people who took an antidepressant were about three times as likely to develop dementia over the following years as those who did not.

However, these studies show an association, not proof that antidepressants cause dementia. Depression itself is linked to a higher risk of dementia, and depression, anxiety or sleep problems can be early signs of dementia that appear years before memory loss is diagnosed. In that case, the antidepressant may be a marker of early disease rather than its cause. Researchers are still working to separate these effects.

Which medications are of most concern?

The clearest concern involves medications with strong anticholinergic effects. These drugs block acetylcholine, a chemical messenger important for memory and attention. In older adults, they can cause confusion, memory problems, dry mouth, constipation, urinary retention and falls.

A large UK study of about 40,000 people with dementia and 280,000 people without it found that long-term use of strongly anticholinergic antidepressants, bladder medications and Parkinson's disease medications was associated with a higher risk of dementia, even when the medications were taken 15 to 20 years before diagnosis. The authors noted that the link might be partly explained by these medications being used for very early symptoms of dementia.

Not all antidepressants are alike. Strongly anticholinergic antidepressants include older tricyclic antidepressants, such as amitriptyline, imipramine and nortriptyline, and the SSRI paroxetine. The American Geriatrics Society Beers Criteria, a widely used list of potentially inappropriate medications for adults aged 65 and older, recommends avoiding these medications in older adults when possible. Most other SSRIs, such as sertraline, citalopram and escitalopram, have little anticholinergic effect.

Many medications for other conditions, such as some bladder, allergy, sleep and stomach medications, also have anticholinergic effects, and their effects add up. A pharmacist can review all medications to reduce this combined "anticholinergic burden". Learn more about another important medication risk for older adults in our article on medications that can cause falls in the elderly.

Why are older adults more sensitive to medications?

With age, the liver and kidneys clear many medications more slowly, body composition changes, and the brain becomes more sensitive to drug effects. Older adults also take more medications on average, which increases the chance of drug interactions. For these reasons, the same dose can lead to higher drug levels and more side effects in an older adult than in a younger person.

Finding an effective antidepressant can also take time. Many people need to try more than one medication or dose before their depression improves, and each attempt can take several weeks.

How do genes affect antidepressants in older adults?

Most antidepressants are broken down by the liver enzymes CYP2D6 and CYP2C19. Genetic variations make some people poor metabolizers, who clear these medications slowly and may build up high drug levels, and others ultrarapid metabolizers, who clear them so quickly that they may not work. In older adults, a genetic tendency to high drug levels adds to the age-related slowing of drug clearance.

• Tricyclic antidepressants. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend that CYP2D6 poor and ultrarapid metabolizers avoid tricyclic antidepressants when possible, and that people with reduced CYP2C19 function receive a lower dose of amitriptyline. This matters because tricyclics are also strongly anticholinergic.
• Paroxetine. CYP2D6 poor metabolizers may have much higher paroxetine levels, and CPIC suggests considering a lower starting dose and slower increases.
• Citalopram and escitalopram. CYP2C19 poor metabolizers have higher drug levels. For citalopram, the US Food and Drug Administration (FDA) recommends a maximum dose of 20 mg a day in CYP2C19 poor metabolizers, the same maximum it recommends for people over 60, because higher levels can affect heart rhythm.
• Sertraline. CYP2C19 poor metabolizers may need a lower starting dose and slower increases.

Other medications can have the same effect as genes. For example, paroxetine, fluoxetine and bupropion strongly block CYP2D6, so a person taking one of them processes other CYP2D6 medications as if they were a poor metabolizer. A pharmacist review that considers both genetic results and all current medications can identify these combined risks.

What can older adults and caregivers do?

• Don't stop an antidepressant suddenly. Stopping abruptly can cause withdrawal symptoms and a return of depression. Talk to the doctor or pharmacist first.
• Ask for a medication review, especially if you take five or more medications, or any medication with strong anticholinergic effects.
• Report new confusion, memory problems or falls to your doctor, as they can be side effects of medications.
• Consider pharmacogenetic testing before starting or changing an antidepressant, to help choose a medication and dose that suit your body.

How can Pillcheck help?

Pillcheck reports on the genes that affect most antidepressants, including CYP2D6 and CYP2C19, as well as many medications for heart disease, pain, digestive and other conditions that older adults often take. A Pillcheck pharmacist reviews each person's results together with all their current medications, taking into account drug interactions and the Beers Criteria, and can share recommendations with their doctor. In a 2020 Pillcheck study in four Ontario long-term care homes, residents were taking 7 to 47 medications each. Pharmacogenetic analysis identified 114 drug therapy problems in 90 residents, 29 of them serious. More than 35% of residents were taking antidepressants, and 64% of them had altered CYP2C19 or CYP2D6 metabolism that could call for a dose adjustment or a different antidepressant. Learn more about the Pillcheck long-term care study. Learn more about Pillcheck for mental health.

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.

Summary

• Studies link antidepressant use in older adults with a higher risk of dementia, but this may partly reflect depression itself or early dementia symptoms, rather than the medications.
• The clearest concern is medications with strong anticholinergic effects, including tricyclic antidepressants and paroxetine. The Beers Criteria advise avoiding them in older adults when possible.
• Older adults clear medications more slowly and often take several medications, which increases the risk of side effects and interactions.
• CYP2D6 and CYP2C19 genes affect how antidepressants are processed, and CPIC and FDA guidance recommends dose changes or alternatives for some people.
• A pharmacist review of genetic results and all medications can help older adults use antidepressants more safely. In Ontario long-term care homes, 64% of residents taking antidepressants had altered CYP2C19 or CYP2D6 metabolism.

Frequently asked questions

Will taking an antidepressant give me dementia?

There is no proof that antidepressants cause dementia. Studies show an association, which may partly reflect depression itself or early dementia symptoms. The clearest concern is with strongly anticholinergic medications, and these can often be replaced with safer alternatives.

Which antidepressants are safer for older adults?

Many SSRIs, such as sertraline, citalopram and escitalopram, have little anticholinergic effect, although they have other risks and dose limits. The best choice depends on the person's health, other medications and genetic results. Talk to your doctor or pharmacist.

Should I stop my antidepressant because of this?

No. Never stop an antidepressant suddenly. Untreated depression also carries risks. Ask your doctor or pharmacist to review your medications.

Is pharmacogenetic testing useful for older adults?

Yes. Older adults often take several medications, and many of them are affected by the same genes. One test can guide current and future prescriptions for antidepressants, pain medications, heart medications and more.

References

1. Kodesh A, Sandin S, Reichenberg A, et al. Exposure to antidepressant medication and the risk of incident dementia. Am J Geriatr Psychiatry. 2019;27(11):1177-1188. doi:10.1016/j.jagp.2019.05.019
2. Richardson K, Fox C, Maidment I, et al. Anticholinergic drugs and risk of dementia: case-control study. BMJ. 2018;361:k1315. doi:10.1136/bmj.k1315
3. 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. doi:10.1111/jgs.18372
4. 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. doi:10.1002/cpt.597
5. 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. doi:10.1002/cpt.2903
6. US Food and Drug Administration. Table of pharmacogenetic associations. fda.gov
7. Dorfman R, London Z, Metias M, Kabakchiev B, Mukerjee G, Moser A. Individualized medication management in Ontario long-term care: clinical impact on management of depression, pain, and dementia. J Am Med Dir Assoc. 2020;21(6):823-829.e5. doi:10.1016/j.jamda.2020.04.009