What the CAMH trial of pharmacogenetics for severe depression teaches us about timing

Pharmacogenetics (PGx) looks at how your genes affect the way your body processes medications. People given the same dose of an antidepressant can have very different levels of the drug in their blood: some may not respond until the dose is increased, while others have troublesome side effects even at a standard dose. A PGx test helps identify these differences before or during treatment.

A Canadian clinical trial led by the Centre for Addiction and Mental Health (CAMH) in Toronto tested whether pharmacogenetic-guided treatment helps people with moderate to severe depression. Its results were encouraging but did not reach statistical significance. Understanding why says a lot about when pharmacogenetic testing is most useful.

What was the CAMH trial?

The GAPP-MDD trial, published in 2022, was a randomized controlled trial at clinics in Canada. Neither the patients nor the people rating their symptoms knew who was in which group. All participants had major depressive disorder and had not responded well to at least one medication in their current episode of depression. On average, they had already tried and stopped 3.6 psychiatric medications during their lives.

All participants gave a cheek swab for a commercial pharmacogenomic test. They were then randomly assigned to one of three groups: two groups whose doctors received a version of the test report to guide treatment, and a group that received usual care without the report. A total of 371 people were randomized, and 276 people with moderate or more severe depression were included in the main analysis. Several of the study's authors were employees of the company that makes the test.

What did the CAMH trial find?

After eight weeks, people whose treatment was guided by the test did better on average than those who received usual care:

Outcome at week 8	Test-guided care	Usual care
Improvement in depression symptoms	27.6%	22.7%
Response (symptoms reduced by at least half)	30.3%	22.7%
Remission (few or no symptoms)	15.7%	8.3%

However, these differences were not statistically significant, at week 8 or at week 24. The trial was stopped early, before it reached its planned size, and the authors calculated that it had less than a 25% chance of detecting a real difference of the expected size. The results were similar in direction and size to those of a larger US trial of the same test, GUIDED, which included 1,167 people. In GUIDED, the main outcome (symptom improvement at week 8) was also not significant, but response (26.0% vs 19.9%) and remission (15.3% vs 10.1%) were significantly better with the test.

Why didn't the CAMH trial show a significant benefit?

Trial size is part of the answer. But the timing of testing matters too. The CAMH trial enrolled people with difficult-to-treat depression who had already been through several rounds of trial and error. By the time they joined, much of the work a PGx test does had already happened:

• Most were already on a genetically suitable medication. At the start of the trial, about 83% of people in the test-guided groups and 81% in the usual-care group were already taking medications without serious gene-drug interactions. The authors noted that this was likely the result of years of trial and error. When most people are already on a medication that suits their genes, a test has fewer mismatches left to correct.
• Treatment-resistant depression is harder to treat by any method. In the large STAR*D study, about 37% of people reached remission with their first antidepressant, 31% with the second, and only 13% to 14% with the third or fourth. People who have already tried several medications are less likely to respond to the next one, whatever guides the choice.
• Genes are only one reason for treatment failure. In people with long-standing depression, other factors, such as other health conditions, life stress and the nature of the illness itself, play a larger role.

Why does testing earlier make more sense?

Pharmacogenetic testing is, by nature, preventive. Its greatest value is in helping choose a suitable medication and dose before a person goes through months of side effects or treatment that doesn't work, not after they have already found a tolerable medication by trial and error.

Research that tests people at the start of treatment supports this approach:

• In the US PRIME Care trial of 1,944 veterans who were starting or switching a single antidepressant, published in JAMA in 2022, 59% of people whose doctors had the test results received an antidepressant with no predicted drug-gene interaction, compared with 26% in usual care. Remission rates over 24 weeks were modestly higher in the test-guided group.
• In the European PREPARE study of about 6,900 people starting a new medication, published in The Lancet in 2023, testing a 12-gene panel before the first prescription reduced clinically relevant side effects by 30%: 21.0% of people with an actionable result had a side effect in the testing group, compared with 27.7% in the usual-care group.

Combining the results of 13 trials with 4,767 people, a 2022 meta-analysis found that people whose antidepressant treatment was guided by PGx testing were about 1.4 times as likely to reach remission as those whose treatment was not. The authors described the effect as modest but significant, and noted that trials differed in the genes tested and in how the results were applied.

What did the Canadian pharmacy trial of Pillcheck find?

In a randomized clinical trial in three Canadian community pharmacies, published in 2021, people with depression or anxiety whose antidepressant treatment was guided by Pillcheck had greater improvement in depression, anxiety and disability over six months than those who received standard treatment. In this trial, a clinical pharmacist reviewed the genetic results and the person's medications and worked with their doctor. Learn more about the Pillcheck pharmacy trial.

What does this mean for people with depression?

• Consider testing early. A PGx test is most useful when a doctor is choosing a first or second antidepressant, so that medications and doses more likely to cause side effects or not work can be avoided from the start.
• Testing still helps later. If you have tried several medications, a test can still explain past side effects or lack of response, and guide future prescriptions. But it is unlikely to solve every problem on its own.
• Expert interpretation matters. Results are most useful when a pharmacist or doctor reviews them together with all your medications, including possible drug interactions, using evidence-based recommendations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for antidepressants.
• Your results last a lifetime. Because your genes don't change, one test can guide medication choices for depression and many other conditions in the future.

How can Pillcheck help?

Pillcheck covers many antidepressants and other mental health medications, as well as medications for pain, heart disease and other conditions. A Pillcheck pharmacist reviews your results together with all your current medications and can share recommendations with your doctor. Canada Life, Medavie Blue Cross and Empire Life include Pillcheck in disability benefits, and Canada Life and Medavie Blue Cross offer plan members a preferred price. Learn more about Pillcheck for mental health and how to get a pharmacogenetic test in Canada.

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

• The CAMH-led GAPP-MDD trial found better outcomes on average with pharmacogenetic-guided treatment, but the differences were not statistically significant. The trial was stopped early and was too small to detect the expected effect.
• Participants had already tried an average of 3.6 medications, and more than 80% were already on genetically suitable medications when the trial started, which left little room for the test to make a difference.
• Pharmacogenetic testing is preventive by nature. Studies that tested people at the start of treatment, such as PREPARE, found fewer side effects.
• Across 13 trials, PGx-guided treatment made remission about 1.4 times as likely.
• Testing is most useful early in treatment, with a pharmacist or doctor to help apply the results.

Frequently asked questions

Did the CAMH trial show that pharmacogenetic testing doesn't work?

No. People in the test-guided groups did better on average, and the results were similar to those of a larger trial in which some outcomes were significantly better. The CAMH trial was too small to confirm the difference statistically, and it enrolled people who had already tried many medications.

When is the best time to get a pharmacogenetic test?

Ideally before starting a new antidepressant, or after the first one hasn't worked or has caused side effects. Testing early can help avoid medications and doses that are more likely to cause problems.

Is it too late to test if I've already tried several antidepressants?

No. Your results can help explain past side effects or lack of response, guide future medication choices and identify drug interactions. Because your genes don't change, the results remain useful for life.

Can a pharmacogenetic test cure depression?

No. It is a tool that helps choose medications and doses. Depression treatment often also includes counselling, lifestyle changes and time to see the full effect of a medication.

References

1. Tiwari AK, Zai CC, Altar CA, et al. Clinical utility of combinatorial pharmacogenomic testing in depression: a Canadian patient- and rater-blinded, randomized, controlled trial. Transl Psychiatry. 2022;12(1):101. doi:10.1038/s41398-022-01847-8
2. Greden JF, Parikh SV, Rothschild AJ, et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: a large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res. 2019;111:59-67. doi:10.1016/j.jpsychires.2019.01.003
3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. doi:10.1176/ajp.2006.163.11.1905
4. Oslin DW, Lynch KG, Shih MC, et al. Effect of pharmacogenomic testing for drug-gene interactions on medication selection and remission of symptoms in major depressive disorder: the PRIME Care randomized clinical trial. JAMA. 2022;328(2):151-161. doi:10.1001/jama.2022.9805
5. Swen JJ, van der Wouden CH, Manson LE, et al. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study. Lancet. 2023;401(10374):347-356. doi:10.1016/S0140-6736(22)01841-4
6. Brown LC, Stanton JD, Bharthi K, et al. Pharmacogenomic testing and depressive symptom remission: a systematic review and meta-analysis of prospective, controlled clinical trials. Clin Pharmacol Ther. 2022;112(6):1303-1317. doi:10.1002/cpt.2748
7. Papastergiou J, Quilty LC, Li W, et al. Pharmacogenomics guided versus standard antidepressant treatment in a community pharmacy setting: a randomized controlled trial. Clin Transl Sci. 2021;14(4):1359-1368. doi:10.1111/cts.12986
8. 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