Why it’s a good idea to test your DNA before starting an add-on antidepressant

Ruslan Dorfman, PhD, MBA30 Oct 2026

Did you know that only about one in three people reach remission with the first antidepressant they try? Many end up switching medications or adding another one. Depression treatment has often involved a lot of "trial and error" to find what works for each person. Clinical trials have shown that using pharmacogenetic testing to guide antidepressant treatment makes people about 40% more likely to reach remission. Here we explain how pharmacogenetic testing can help when choosing an "add-on" medication to boost treatment and speed recovery from depression and anxiety.

How does depression treatment usually start?

Canadian guidelines list several first-line antidepressants, including SSRIs such as citalopram, escitalopram and sertraline, SNRIs such as venlafaxine and duloxetine, and others such as bupropion, mirtazapine and vortioxetine. Psychotherapy, such as cognitive behavioural therapy (CBT), is also a first-line option and works well together with medication. If the first antidepressant does not work well enough, the next step is usually to adjust the dose, switch to another antidepressant or add a second medication. Each added medication or supplement also adds the chance of drug interactions, so combinations should be chosen carefully.

Which add-on antidepressants work best?

A 2022 meta-analysis of 39 trials found that combining two antidepressants worked better than a single antidepressant, without more people stopping treatment because of side effects. Adding mirtazapine, trazodone or mianserin (medications that block α2-autoreceptors) to an SSRI or SNRI worked better than other combinations. Mianserin is not available in Canada. Bupropion is another commonly used add-on, but in this analysis, adding bupropion to an SSRI did not work better than the SSRI alone. Bupropion on its own can be an effective treatment for people who could not tolerate citalopram, sertraline, paroxetine, fluvoxamine or other SSRIs.

If these combinations do not work, a psychiatrist may add an antipsychotic, such as aripiprazole (Abilify), brexpiprazole (Rexulti) or quetiapine XR (Seroquel XR), to the antidepressant for treatment-resistant depression.

Why does your DNA matter for add-on antipsychotics?

Aripiprazole and brexpiprazole are broken down mainly by the CYP2D6 enzyme. Their drug labels recommend a lower dose, often half the usual dose, for people who are CYP2D6 poor metabolizers, and further dose changes when CYP2D6 or CYP3A4 blockers are also taken. This matters because some antidepressants, such as fluoxetine, paroxetine and bupropion, strongly block CYP2D6 and can raise aripiprazole and brexpiprazole levels. Quetiapine is broken down by CYP3A4, and strong CYP3A4 blockers can raise its levels a lot. Knowing your genes before adding one of these medications helps your doctor choose the right dose from the start.

Before adding another pill, why didn't the first antidepressant work?

There are many reasons why an antidepressant may not work or may cause side effects. Almost all antidepressants are broken down by liver enzymes called cytochromes P450 (CYP450 for short). If you are a rapid or ultrarapid metabolizer, your liver clears the medication quickly, so it may not work at the usual dose. If you have strong side effects, you may be a poor or intermediate metabolizer, so the medication builds up in your body. You can be a slow metabolizer for some medications and a fast metabolizer for others, so one antidepressant may not work for you while another causes side effects. That is why finding the right prescription can take months of trial and error.

graphical depiction of the effect of standard dosing on different metabolizer types

How does pharmacogenetic testing increase the chance of success?

A pharmacogenetic test shows how your body processes different medications. Expert reviews now recognize it as an established tool for guiding depression treatment, and a meta-analysis of 13 clinical trials found that people whose antidepressant treatment was guided by pharmacogenetic testing were about 40% more likely to reach remission.

With pharmacogenetic results, you and your doctor can better understand how your body clears different antidepressants and other medications. Tests with broad coverage, such as Pillcheck, cover the key enzymes that break down antidepressants, antipsychotics, benzodiazepines and other medications used for depression and anxiety. 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 and recommends which medications may work better for you and which to avoid if possible.

How gene variations change the right antidepressant dose: some people need a higher dose, some the standard dose, and others a lower dose or a different drug

What else can help treat depression?

In a 2022 commentary, psychiatrists Roy H. Perlis and Maurizio Fava argued that the STAR*D study of treatment sequences should be repeated with the newer tools now available. Today, those tools include pharmacogenetic testing to help choose and dose medications, digital and therapist-guided CBT alongside medication, and newer add-on options for people who do not respond. A psychiatrist can also re-assess the diagnosis and recommend other treatments when needed.

Summary

Only about one in three people reach remission with their first antidepressant.
Your DNA affects how your body processes many antidepressants and add-on medications.
Adding mirtazapine or trazodone to an SSRI or SNRI works better than other combinations. Adding bupropion did not improve results in a large analysis.
Aripiprazole and brexpiprazole need lower doses in CYP2D6 poor metabolizers and with some antidepressants that block CYP2D6.
Pharmacogenetic testing with a pharmacist review can help your doctor choose the right antidepressant and add-on before starting.
CBT should be used along with medication to improve depression treatment.

Frequently asked questions

Is it better to switch antidepressants or add a second one?

Both are options, and the right choice depends on how well the first medication worked, its side effects and your history. Your doctor may also adjust the dose first. Pharmacogenetic testing can show whether the first medication may have been cleared too quickly or too slowly.

Is it safe to take two antidepressants together?

Some combinations are commonly used and well studied, but combining medications increases the chance of interactions, including serotonin syndrome. Only combine medications under your doctor's supervision.

Why would my doctor add an antipsychotic for depression?

Low doses of some antipsychotics, such as aripiprazole, brexpiprazole and quetiapine XR, are approved as add-on treatments when depression does not respond well enough to antidepressants alone. Their doses depend on your CYP2D6 or CYP3A4 status and other medications.

Can a genetic test tell me which add-on will work?

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

See how Pillcheck helps you and your healthcare provider choose the right mental health medications: