Antidepressants: Understanding and Mitigating the Risks of Side Effects

Ruslan Dorfman, PhD, MBA30 Oct 2026

Every medication has benefits and risks, and antidepressants are no exception. Some people delay seeking help for depression because they worry about side effects. Others stop treatment early because of side effects they did not expect. Knowing which side effects are common, which are serious and how to reduce them can make treatment safer and easier to stay on. Your genes are one piece of that puzzle, because they affect how your body processes many antidepressants.

Why can finding the right antidepressant take time?

Antidepressants include several classes that work in different ways: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and others, such as bupropion, mirtazapine and vortioxetine. About 30 antidepressants are available in Canada. They are also used for anxiety, chronic pain, eating disorders and other conditions.

On average, antidepressants work about equally well, but each person's response varies a lot. In the large STAR*D study, about one in three people reached remission with their first antidepressant, citalopram. Those who did not often needed to try more medications or combinations, and the chance of remission fell with each additional step. This "trial and error" can take months. For mild depression, psychotherapy is often tried first. For moderate to severe depression, medication, psychotherapy or both are recommended.

What are the common side effects of antidepressants?

Many side effects are mild and ease within the first few weeks. Common ones include:

Nausea, upset stomach or diarrhea
Headache
Trouble sleeping or feeling sleepy, depending on the medication
Vivid dreams
Sweating, dry mouth or dizziness
Feeling emotionally "flat" or less able to feel strong emotions
Sexual side effects, such as lower desire or delayed orgasm
Weight changes

Sexual side effects are among the most common reasons people stop treatment. In one large study, between 58% and 73% of people taking SSRIs or venlafaxine reported a sexual side effect, compared with much lower rates for mirtazapine, bupropion and moclobemide. Read more about antidepressants and sexual health.

Weight changes vary by medication. In a large UK study, people prescribed antidepressants were about 20% more likely to gain at least 5% of their body weight over the following years. Mirtazapine, paroxetine and tricyclic antidepressants are more often linked to weight gain, while bupropion is more often linked to weight loss.

What are the serious risks of antidepressants?

Suicidal thoughts in young people. In children, teenagers and young adults under 25, antidepressants can increase suicidal thoughts and behaviours in a small number of people, especially in the first weeks. This means close monitoring, not avoiding treatment. Read more about choosing antidepressants for teenagers and seniors and how genetic testing can reduce suicide risk in youth.
Mania in bipolar disorder. Antidepressants can trigger mania or hypomania in people with bipolar disorder, whose depression can look the same as regular depression. Tell your doctor if you have ever had periods of very high energy or little need for sleep, or if bipolar disorder runs in your family.
Serotonin syndrome. Combining serotonin-acting medications, such as an SSRI or SNRI with tramadol, triptans for migraine, linezolid, lithium or St. John's wort, can cause agitation, fever, sweating, tremor and muscle stiffness. It needs urgent care.
Bleeding. SSRIs and SNRIs raise the risk of stomach bleeding, especially with NSAIDs such as ibuprofen, aspirin or blood thinners.
Low sodium. SSRIs and SNRIs can lower sodium levels, especially in older adults, causing confusion, unsteadiness and falls.
Heart rhythm. Citalopram and escitalopram can affect the heart rhythm at higher doses, so lower maximum doses are recommended for older adults.
Discontinuation symptoms. Stopping an antidepressant suddenly can cause dizziness, "brain zaps", irritability, flu-like symptoms and sleep problems. Antidepressants should be reduced slowly with your prescriber's help.

Are antidepressants safe during pregnancy?

This is an important decision that should be made with your doctor. Some antidepressants have been linked to a small increase in certain risks, but untreated depression during pregnancy also carries risks for both parent and baby. For many people, continuing treatment is the safer choice. Read more about antidepressants during pregnancy and how your DNA can help.

How can you lower the risk of side effects?

Start at a low dose and increase slowly, as your prescriber advises.
Take the medication at the time of day that suits it, for example in the morning if it keeps you awake, or with food if it upsets your stomach.
Give it time. Many side effects ease after two to four weeks, while the benefits build over four to eight weeks.
Tell your doctor and pharmacist about all your medications, supplements and cannabis use, to avoid interactions.
Do not stop suddenly. If side effects are a problem, ask about lowering the dose, changing the timing or switching.
Combine medication with psychotherapy, exercise and good sleep, which support recovery.

How do genes affect antidepressant side effects?

Liver enzymes control how quickly antidepressants are cleared, and the genes for these enzymes vary. If you clear a medication slowly, levels can build up and cause more side effects. If you clear it quickly, it may not work at the usual dose. The Clinical Pharmacogenetics Implementation Consortium (CPIC) gives gene-based recommendations:

CYP2C19 affects citalopram, escitalopram and sertraline. In the STAR*D study, people with reduced CYP2C19 activity were less likely to tolerate citalopram, and those who did tolerate it were more likely to reach remission.
CYP2D6 affects paroxetine, fluvoxamine, venlafaxine, vortioxetine and tricyclic antidepressants. Some studies have linked CYP2D6 ultrarapid metabolism, often caused by extra copies of the gene, to a higher risk of repeat suicide attempts.
CYP2B6 affects sertraline and bupropion.

Other medications can also speed up or slow down these enzymes. For example, bupropion, fluoxetine and paroxetine strongly block CYP2D6 and can raise the levels of other medications that CYP2D6 breaks down.

How can a pharmacogenetic test help?

A Pillcheck test shows how your genes affect antidepressants, anxiety medications, pain relievers and many other medications. 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. A Pillcheck pharmacist reviews your results together with all your medications, checks for interactions and recommends options and doses to discuss with your doctor. Genetic testing cannot remove all risk of side effects, but it can help you start with a medication and dose that suit your body.

Summary

Finding the right antidepressant can take time, and about one in three people reach remission with the first medication.
Common side effects, such as nausea, headache and sleep changes, often ease within a few weeks. Sexual side effects and weight changes are common reasons people stop treatment.
Serious risks include suicidal thoughts in people under 25, mania in bipolar disorder, serotonin syndrome, bleeding, low sodium and heart rhythm effects.
Starting low, avoiding interactions and never stopping suddenly help lower the risk.
CYP2C19, CYP2D6 and CYP2B6 testing, with a pharmacist review, can help choose an antidepressant and dose that suit you.

Frequently asked questions

How long do antidepressant side effects last?

Many common side effects, such as nausea and headache, ease within two to four weeks. Others, such as sexual side effects or weight gain, may continue. Talk to your doctor if side effects do not improve.

Which antidepressant has the fewest side effects?

No antidepressant is best for everyone. Side effects differ between medications, and your genes, age, health and other medications all matter. A pharmacogenetic test can help narrow the choice.

Can I stop my antidepressant if I feel better?

Talk to your prescriber first. Stopping suddenly can cause discontinuation symptoms and increases the risk that depression will return. Most people continue for at least six to twelve months after feeling well, then reduce slowly.

Can a genetic test tell me which antidepressant will work?

No test can promise that. A pharmacogenetic test shows how your body processes many antidepressants, which helps your doctor choose a medication and dose with a better chance of working and fewer side effects.