Gene testing can optimise the drug treatment of young people with mental disorders

Disease and treatment 13. dec 2021 7 min Associate professor, Research Pharmacist Christiane Gasse Written by Sybille Hildebrandt

A new study in Denmark shows that young people with mental disorders are often treated with drugs that are known to be affected by each individual’s genetic make-up in metabolising and reacting to these drugs. The researchers suggest that systematic testing of young people with mental disorders may optimise treatment.

Pharmacogenetic drugs are drugs for treating mental disorders that individuals metabolise differently because of genetic variation and are prescribed very frequently to children and young adults. This is the main conclusion of a registry study funded by the Novo Nordisk Foundation and others carried out at the Department of Clinical Medicine of Aarhus University. The results were recently published in Pharmacopsychiatry. The first author was Carin Lunenburg and Christiane Gasse was the senior author, both from Aarhus University and Aarhus University Hospital Psychiatry.

“The results elucidate the frequency of use of pharmacogenetic drugs in Denmark and by which patients. Young people with mental disorders often use these types of drugs,” explains Christiane Gasse.

Systematic pharmacogenetic testing

Pharmacogenetics describes the genes of individuals that encode proteins that convert, transport or are a target for drugs.

Christiane Gasse says that young people with mental disorders might benefit from pharmacogenetic testing. This shows whether they have the gene variants that trigger rapid or slow metabolism of pharmacogenetic drugs, which are drugs that are more or less effective depending on the genes of each individual.

By testing young people shortly after being diagnosed with a mental disorder, doctors can optimise treatment at the time of diagnosis instead of the doctor and patient experimenting by adjusting the dose to an appropriate level over several weeks.

“Systematic pharmacogenetic testing for these differences in drug metabolism seems to have potential for improving the benefits of treatment with pharmacogenetic drugs. Since our study shows that many young people use these drugs, even a very small positive effect of advanced genetic testing could have a significant overall clinical effect,” says Christiane Gasse.

Although pharmacogenetic testing has been an option for many years, Christiane Gasse says that it is not yet used very much. She hopes that the study can help to make doctors aware that using this method for young people is helpful.

“In addition, we want to identify the patient groups on which doctors can focus most for better implementing pharmacogenetic testing or determining what is specifically needed to implement it, so that it benefits not only the patients consulting a few doctors but all relevant people,” she says.

Linking new and old results

The fact that pharmacogenetics affects young people who have been diagnosed with a mental disorder is a simple message. But confirming this has been extremely complex, requiring that Christiane Gasse and colleagues map the use of pharmacogenetic drugs among both people with mental disorders and a representative population sample.

The researchers ultimately compared these findings with their previous mapping of genetic variants among people with mental disorders based on data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). To map the use of pharmacogenetic drugs among the general population, Christiane Gasse and colleagues retrieved data from the Danish Neonatal Screening Biobank, which contains newborn blood samples from all residents of Denmark born after 1982.

The researchers randomly selected 30,000 anonymised individuals as a representative population sample and then found 56,065 individuals who had contact with Denmark’s psychiatric hospitals because of mental disorders – primarily those with at least one of the major mental disorders schizophrenia, depression, attention-deficit/hyperactivity disorder (ADHD) and autism in the Danish National Patient Registry, which contains information about the contacts with hospitals among all residents of Denmark.

Almost back to birth

The researchers determined the medicine used by young people with and without a mental disorder by linking the data with people’s age and sex provided by Statistics Denmark and information on all pharmacy prescriptions in the Danish National Prescription Registry.

They then compared the drugs used by young people with and without a mental disorder with the results from the previous study in which they mapped the pharmacogenetic genes of the same people. .

“Linking the results from these studies shows how people’s use of these pharmacogenetic drugs is associated with their genes almost back to birth – at least for those born since 1995, when the Danish National Prescription Registry was established,” explains Christiane Gasse, who emphasises that the registry research was carried out completely anonymously and was approved in advance by the owners of the data and the relevant authorities.

Use of drugs reflects mental disorders

The new study reveals considerable differences in treatment patterns for the selected pharmacogenetic drugs among children and young adults with a mental disorder compared with their peers of the population without the disorders. People without a mental disorder often use antacids and various types of painkillers, whereas people already diagnosed with a mental disorder in childhood have markedly higher consumption of psychotropic drugs, especially drugs such as atomoxetine for ADHD and citalopram for depression.

Christiane Gasse mentions that the study revealed great differences in the use of at least one pharmacogenetic drug: lowest among males without a mental disorder (23%) and highest among females with schizophrenia (97%).

The mean number of pharmacogenetic drugs used was 1.2 for males without mental disorders and 5.6 for people with schizophrenia. The study also showed that males with ADHD or autism are the youngest first-time users of pharmacogenetic drugs, with a mean age of 11.6 years. The prevalence of pharmacogenetic drugs linked to more than one gene ranged from 25% among males without mental disorders to 94% among females with schizophrenia.

Improving response or reducing side-effects

Christiane Gasse hopes that the mapping can create awareness about the benefits of pharmacogenetic testing, since this can enable doctors to adjust the dosage according to how well a person responds to medication.

“A paradigm within clinical pharmacology is that the doctor must find the right dose for each individual at the right time. Doctors strive to follow this principle as far as possible. But many doctors are not sufficiently aware that pharmacogenetics can be a way to achieve this goal. Our studies show how many children and adolescents have a specific pharmacogenetic profile, and the doctors responsible for treatment have the opportunity to adjust the dosage based on pharmacogenetic testing,” says Christiane Gasse, who adds that doctors can adjust the dosage based on how well a person metabolises the drugs, increasing the response rate or reducing the side-effects even before treatment starts. This eliminates the risks and discomfort associated with adjusting the dose by trial and error for weeks or months.

“We hope that these results can make doctors more aware that pharmacogenetic measures can benefit patients, finding the right dose earlier and protecting against unnecessary side-effects,” she explains.

Prompt test results needed

The new study therefore suggests that doctors may benefit from using pharmacogenetic testing, but doubts still exist about how exactly this should happen, says Christiane Gasse.

“When mental symptoms emerge, pharmacogenetic testing may be too late since medication is often needed rapidly. This has led researchers to suggest whether one logical measure could be to determine everyone’s phenotypes in Denmark in pharmacogenetic testing shortly after birth,” explains Christiane Gasse.

She says that there are many opinions about the best and most ethical strategy. In addition, there is disagreement about whether the current pharmacogenetic testing is good enough, since the translation of gene expression and determination of a person’s phenotype is still being developed and the results take up to 8 days.

“Whether a doctor chooses pharmacogenetic testing largely depends on how rapidly the test result is available. In acute situations, waiting weeks for results is not an option. Whether the doctor performs the testing obviously depends largely on how quickly the results are available,” says Christiane Gasse, who hopes that unresolved questions will soon be answered so that pharmacogenetic testing becomes even more accurate and more useful.

“The great advantage of pharmacogenetic testing is that each individual only needs to be tested once for life. The test reveals their phenotype, such as whether the liver metabolises drugs quickly or slowly. People can then inform their doctor about this, enabling individual treatment,” she explains.

Genetics and other factors affecting drug metabolism and treatment outcomes

“We have not yet investigated how genetics affects treatment outcomes compared with other factors. But future studies will hopefully elucidate the extent to which genetic factors affect treatment response, considering other clinical factors affecting treatment response and drug metabolism such as other underlying diseases, age, sex, clinical and demographic conditions and frequency of contact with the healthcare system. Only then can we really determine the role of genetics,” says Christiane Gasse.

One psychiatric hospital whose psychiatrists can request pharmacogenetic testing is the Mental Health Services of the Capital Region of Denmark, where Thomas Werge, Clinical Professor and head of the Institute of Biological Psychiatry, established this option. He advised Christiane Gasse and her team based on his experience in using pharmacogenetic testing to optimise treatment with psychotropic drugs and co-authored the scientific article.

“People metabolise certain drugs at different rates. Since genetics is one factor determining these differences, using genetics to optimise treatment is logical,” explains Thomas Werge.

Examining genetics is relevant

Pharmacogenetic testing is not the best way to measure how rapidly individuals metabolise a drug. The optimal way is to measure this directly. But Thomas Werge considers pharmacogenetic testing to be a rapid way to determine how quickly a person metabolises pharmacogenetic drugs, since it only needs to be done once and can be done before treatment begins.

“This has been done in many parts of the world, but we were among the first to start doing it many years ago,” says Thomas Werge, who indicates that the study shows that many young people will be prescribed standard drugs at other times in their lives, and pharmacogenetic testing could contribute to optimising their medication use.

He thinks that the study therefore provides a qualified target for how many young people receive pharmacogenetic medication and therefore should be tested genetically. “The study provides a map that identifies very large groups for whom pharmacogenetic testing might make sense and shows that the overall effect of pharmacogenetic testing can be significant and relevant for some individuals, even if the average effect per person is minimal.”

The testing could be used to improve the treatment, such as 5% better, for all these patients and to calculate the possible gain by adjusting the treatment to each individual by increasing or decreasing the dose depending on how rapidly they metabolise these drugs.

“If we do not know anything about a person in advance, we can use genetics alone to determine each person’s basic situation and start at a higher dose because they are effective at metabolising drugs – or vice versa. This avoids starting with too high a dose, thereby triggering too many unnecessary side-effects or starting at too low a dose and not achieving the desired effectiveness. Optimising treatment effectiveness is absolutely crucial for people with a mental disorder, who are often tormented by their disorder,” explains Thomas Werge.

Life-time actionable pharmacogenetic drug use: a population-based cohort study in 86 040 young people with and without mental disorders in Denmark” has been published in Pharmacopsychiatry. In 2017, the Novo Nordisk Foundation awarded a grant to Christiane Gasse for the project Pharmacogenetic Testing: Who and Why? Pharmacoepidemiological Descriptive and Analytical Studies of Pharmacogenomics of Treatment Response in Psychiatry and in the General Population.

Weaknesses of the study

The results must be interpreted with caution since the Danish National Prescription Registry was established in 1995 but the Danish Neonatal Screening Biobank was established in 1981. Thus, the researchers always had to distinguish between the specific cohorts they were analysing. Their ability to analyse the data was limited by the fact that only the one cohort born after 1995 contains lifetime data up to the age of 21 years. Since Christiane Gasse and colleagues only have a complete overview of the drugs the selected cohort received after 1995, they do not know what drugs people born between 1981 and 1995 used in childhood.

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