Why do the same antidepressants work differently? The true meaning of "20.7% of people can metabolize them typically" — What can be learned from genetic testing in psychiatry

Genetic Clues to "Medication Mismatch"—Psychiatric Drugs and Individual Differences in Metabolism

Despite taking the same medication, one person may find relief from symptoms, while another struggles with severe drowsiness or discomfort. Even after changing medications, satisfactory treatment remains elusive.

For those who have used psychiatric medications, such "differences in effectiveness" are a pressing issue.

One factor gaining attention is the individual differences in how the body processes medication. Could pharmacogenetic testing, which examines genetic information to understand drug metabolism characteristics and aids in prescription decisions, reduce the trial and error in medication selection?

The German news site "AD HOC NEWS" highlighted genetic differences in metabolic enzymes related to psychiatric drugs, introducing a study where 20.7% of people were classified as having "standard metabolism."

However, misinterpreting this figure can lead to unnecessary anxiety. It's important first to confirm what the study actually investigated.

The "20.7%" is not the percentage of people for whom the medication is effective

The related original research involved 154 individuals hospitalized in Germany for mood or anxiety disorders who underwent genetic testing.

Among 145 patients with the necessary data on two metabolic enzymes, 30 had no genetic characteristics requiring prescription adjustments for either CYP2D6 or CYP2C19. This corresponds to 20.7%.

It's crucial to understand that this study did not count "people in the general population for whom psychiatric drugs work normally." The subjects were inpatients tested in a specific medical setting and do not represent the entire patient population in Japan.

Moreover, finding a genetic characteristic does not automatically mean the current medication is inappropriate. The clinical significance varies depending on how much the enzyme is involved in drug processing and its specific characteristics.

Conclusions such as "about 80% do not respond to medication" or "about 80% receive incorrect prescriptions" cannot be drawn from this figure.

The study indicates that individual differences in drug metabolism were widely present in this patient group.

The same dosage does not mean the same amount remains in the body

CYP2D6 and CYP2C19 are enzymes involved in drug metabolism. While their names may seem complex, they are easier to understand when considered as part of the body's process for handling drugs.

Genetic differences mean some people have weaker enzyme activity, while others have stronger activity.

If metabolism is slow, the blood concentration of the drug may become high, leading to side effects. Conversely, if metabolism is fast, maintaining an adequate concentration can be challenging. However, the mechanism varies for each drug, as substances produced by metabolism can also have therapeutic effects.

Therefore, it's not as simple as saying, "People with slow metabolism should reduce all medications."

The information obtained from testing serves as a clue for selecting specific drugs and dosages. It is not an answer to identify "the one drug that will definitely work."

Even with the same genes, drug interactions can alter metabolism

Another aspect not to overlook is the impact of concomitant medications.

Even if standard metabolic capacity is predicted from genetic information, another drug might inhibit enzyme activity, slowing down actual metabolism. This discrepancy between genetic predictions and actual function is known as "phenoconversion."

Thus, prescription decisions cannot be made solely based on test results. Current drug interactions must also be considered.

"Therapeutic Drug Monitoring (TDM)" plays a complementary role here. It involves measuring drug concentrations in the blood and interpreting these values to aid treatment.

While genetic testing provides information predicting metabolic characteristics, TDM offers insights into the actual state within the body. However, not all drugs benefit equally from such measurements, and the necessity of testing varies depending on the drug and situation.

Will genetic testing improve treatment? Expectations and limitations shown by research

Understanding metabolic differences and improving symptoms through testing should be considered separately.

The "PRIME Care" trial in the U.S., published in 2022, showed that using genetic test results in clinical practice reduced prescriptions where drug-gene interactions were predicted.

However, the effect on achieving "remission," where symptoms are sufficiently alleviated, was limited. While there was an advantage for the group using testing throughout the 24-week analysis, there was no statistically significant difference in remission rates when comparing only at the 24-week point.

Research continues beyond this.

A randomized trial involving 1,460 adults and children, published in May 2026, focused on evaluating the effect on those with metabolic characteristics requiring prescription adjustments. Prescriptions based on genetic information did not surpass usual clinical practice in improving depressive symptoms at the three-month mark, but the remission rate was higher at six months.

These results suggest the potential usefulness of testing, but also indicate that "immediate improvement upon testing" cannot be guaranteed.

Determining which patients benefit from testing and at what stage, as well as the differences in recovery and life beyond the short term, are necessary to assess the value of testing.

Voices on social media express both "helpfulness" and "limitations"

On the overseas online forum Reddit, there are both expectations and cautious opinions regarding genetic testing for antidepressants.

The following is a summary of public posts on the same theme, not direct reactions to the German article.

One poster shared that after trying over a dozen antidepressants, genetic testing helped them find a medication that felt effective. Despite feeling burdened by the cost of testing, they valued it as an opportunity to reassess treatment.

Conversely, another discussion highlighted that while genetic testing helps identify considerations regarding drug metabolism, it does not determine which antidepressant will work best.

When treatment trials drag on, it's natural to want "any clue to guide choices." This urgency is conveyed through such posts.

However, these posts are self-reported and not verified by third parties regarding diagnosis, test content, or subsequent treatment progress. Neither positive nor disappointing experiences alone can prove the overall effectiveness of testing.

Do not apply overseas percentages directly to Japan

When reading this news for a Japanese audience, it's important to note that the frequency of genetic characteristics varies among populations.

For example, past studies targeting Japanese individuals have also found a certain percentage predicted to have low CYP2C19 metabolic capacity. However, this frequency varies depending on the study subjects and methods.

It is not appropriate to introduce the "20.7%" obtained from a specific group of hospitalized patients in Germany as the percentage for Japanese people.

The same applies to systems. The original article discusses cost burdens and operational challenges in Germany, but this does not indicate Japan's insurance coverage or testing framework.

When considering testing in Japan, it's necessary to individually confirm whether the results can be applied to the medications one is taking, whether medical institutions can accommodate it, and how costs and result explanations will be handled.

Additionally, interpreting "there are no guidelines overseas either" is not accurate. The international expert organization CPIC has already published guidelines for utilizing genetic information in prescribing some antidepressants. The original article's description of antipsychotics and the guidelines for antidepressants should be read separately.

Turning "medication mismatch" into shareable information during consultations

What should be taken away from this news is not to hastily apply for testing, but rather the perspective that "there are verifiable individual differences in drug reactions."

When consulting about treatment, organizing information such as the following can help convey the troubling situation:

• Which medications were taken, for how long, and at what dosage
• Which symptoms improved and which remain
• When symptoms suspected as side effects began
• Whether other prescription drugs, over-the-counter medications, or supplements are being used

Based on this, one can ask the doctor, "Could drug interactions or metabolic effects be considered?" or "Would measuring blood concentration or genetic testing be a decision-making factor in my treatment?"

It is advisable to avoid stopping medication or changing dosages based on self-judgment from test results or news.

Personalizing psychiatric medication is not achieved solely through genetic information. Treatment is adjusted by combining the effects and difficulties felt by the patient, past progress, drug interactions, and necessary tests.

The patient's experience of "how they felt with this medication" is also crucial information for this purpose.

Sources and References

1. AD HOC NEWS: Introduction of challenges in utilizing tests and cost burdens in Germany for CYP2D6 and CYP2C19.
   https://www.ad-hoc-news.de/wissenschaft/cyp2d6-und-cyp2c19-nur-20-7-prozent-bauen-psychopharmaka-regulaer-ab/70289751

2. Original research targeting hospitalized patients in Germany. Background of the "20.7%" among 154 subjects, with necessary data for 145.doi.org
   https://pubmed.ncbi.nlm.nih.gov/38493365/

3. CPIC guidelines on antidepressants (2023). Explanation of the use of genetic information, metabolism and blood concentration, and phenoconversion due to concomitant drugs.PMC
   https://pmc.ncbi.nlm.nih.gov/articles/PMC10564324/

4. Consensus guidelines on TDM in the field of psychoneuropharmacology. Methods to utilize measurements and interpretations of blood drug concentrations in treatment.PubMed
   https://pubmed.ncbi.nlm.nih.gov/28910830/

5. PRIME Care randomized trial (JAMA, 2022). Verification of prescriptions using genetic testing and effects on depression remission.JAMA Network
   https://jamanetwork.com/journals/jama/fullarticle/2794053

6. Randomized trial of antidepressant prescriptions based on genetic information (JAMA Network Open, 2026). Results on symptom improvement at three months and remission rates at six months.JAMA Network
   https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2848678

7. Study on CYP2C19 genetic polymorphisms in the Japanese population. Reference material indicating genetic individual differences in drug metabolism in Japan.PubMed
   https://pubmed.ncbi.nlm.nih.gov/9631918/

8. Reddit: Positive evaluation of drug treatment after testing. Summary of individual posts as voices from social media.genesight testing
   https://www.reddit.com/r/antidepressants/comments/1dyl39j/

9. Reddit: Discussion on the limitations of what testing can predict. Reference for opinions distinguishing drug metabolism from treatment effects.reddit.com
   https://www.reddit.com/r/antidepressants/comments/trs3k7/