Many Americans in pursuit of anxiety relief find themselves on a carousel of different medications. (Credit: Shidlovski on Shutterstock)
Schizophrenia Genes Reveal Who Benefits From Antihistamines for Anxiety
In A Nutshell
- DNA-based scores gave small clues about who might stay on one anxiety med versus need to switch.
- With benzodiazepines, higher depression-linked scores were tied to needing more than one medication.
- With antihistamines, anxiety and schizophrenia–linked scores pointed to needing multiple meds.
- Antidepressants were harder to predict overall; a signal showed up only in women. Results come from prescriptions, not symptom tests.
Millions of Americans with anxiety and depression know the frustrating routine. Try an antidepressant, wait weeks to see if it works, then switch to another when it doesn’t. Only about one-third of anxiety patients find relief with their first medication, leaving the rest cycling through multiple drugs while their symptoms persist.
A study published in Biological Psychiatry: Global Open Science suggests genetics could help break this cycle. Researchers analyzed 2,515 people with anxiety or depression symptoms in Sweden and found that specific genetic risk scores predicted who would stay on one medication versus who would switch or add others, based on prescription records. In short, the research examines genetic prediction of treatment response across different types of anxiety medications.
Antidepressants like selective serotonin reuptake inhibitors remain the first-line treatment for both anxiety and depression, but benzodiazepines and antihistamines are also commonly prescribed for anxiety symptoms. Finding an effective treatment often requires months or even years of trial and error. Genetic testing could identify who will respond to which medication before treatment begins, potentially saving patients considerable time and suffering.
How Genetic Risk Scores Predicted Treatment Success
Researchers used data from the Swedish Twin Registry, linking genetic information to prescription records from 2005 to 2018. They divided participants into responders (those who stayed on a single medication) and nonresponders (those who switched or added medications). These are prescription-based outcomes, not direct symptom ratings.
Of the 2,515 participants, 1,037 remained on monotherapy: 555 received antidepressants, 169 received benzodiazepines, and 313 received antihistamines. The remaining 1,478 required multiple medications.
The research team calculated 42 different polygenic risk scores for each participant. These scores estimate genetic predisposition based on thousands of genetic variants, including those for major depressive disorder, anxiety disorders, schizophrenia, ADHD, and various personality traits.
Patients prescribed benzodiazepines as their only medication had lower genetic risk scores for depression symptoms compared to those needing multiple drugs. Higher depression genetic scores were associated with a 29% increased likelihood of requiring additional medications.
For antihistamines, higher genetic scores for lifetime anxiety disorder and for schizophrenia were linked to needing multiple medications, even after adjusting for co-occurring anxiety and depression.
None of the genetic scores predicted response to antidepressants in the full sample, though a depression score did predict response in women when analyzed separately.
What Real-World Prescription Patterns Revealed
Rather than controlled experiments, researchers examined actual treatment decisions made by doctors and patients over many years. Patients prescribed benzodiazepines stayed on their medication for an average of 284 days, with nearly all having anxiety symptoms. Antidepressant users remained on medication much longer, averaging 1,021 days, while antihistamine users averaged 204 days.
The multiple-medication group stayed on treatment longest at 1,744 days, suggesting more persistent or severe symptoms. Benzodiazepines work quickly but carry dependence risks and are considered second-line treatments. Antihistamines have shown effectiveness for generalized anxiety disorder with different side effects than antidepressants.
Why Schizophrenia Genes Matter for Anxiety Treatment
One surprising finding involved the schizophrenia genetic risk score predicting antihistamine response. Anxiety and depression share substantial genetic overlap (correlation of 0.80), while major depression shares similarities with schizophrenia, ADHD, and bipolar disorder (correlations around 0.40).
This doesn’t suggest people with anxiety have schizophrenia. Rather, some genetic variations influence risk for multiple conditions and may affect medication response. Models that included all the genetic scores explained 11.7% of the variation for benzodiazepines and 8.4% for antihistamines. The extra lift from genetics over basic factors was modest.
The Antidepressant Puzzle Remains Unsolved
The lack of genetic prediction for antidepressant response contrasts with previous studies. One large study using UK health records found that genetic risk for ADHD predicted poorer antidepressant response, while another linked the personality trait openness to better response.
Several factors might explain this study’s weaker findings for antidepressants. The antidepressant group was more varied, including people with anxiety, depression, or both. Benzodiazepines and antihistamines share sedative effects, while antidepressants work through different mechanisms. Doctors might also prescribe benzodiazepines more selectively due to addiction risks.
The research adds to growing evidence that genetic information could eventually guide treatment decisions. Rather than waiting weeks or months to see if a medication works, genetic testing might identify better options from the start, sparing patients the costs, side effects, and frustration of cycling through treatments while managing debilitating symptoms.
Disclaimer: This article is for general information only. It is not medical advice and does not replace care from a licensed clinician. Never start, stop, or change a medication without talking to your healthcare professional. Genetics influence risk but do not determine individual outcomes.
Paper Summary
Methodology
Researchers identified 2,515 individuals from the Swedish Twin Registry who had been prescribed medications for anxiety and/or depression between 2005 and 2018. All participants had provided DNA samples genotyped using the Illumina Global Screening Array. The team calculated 42 polygenic risk scores for each person, including scores for psychiatric diagnoses and psychological traits. Treatment response was defined as staying on a single medication (monotherapy) versus switching to or adding medications (multitherapy). Researchers used logistic regression to test whether genetic scores predicted monotherapy versus multitherapy for antidepressants, benzodiazepines, and antihistamines, controlling for age, sex, and genetic ancestry.
Results
Among participants, 1,037 received monotherapy (555 antidepressants, 169 benzodiazepines, 313 antihistamines) while 1,478 required multiple medications. For benzodiazepines, higher depression symptom scores predicted needing multiple medications (odds ratio 1.29). For antihistamines, higher genetic risk scores for lifetime anxiety disorder (odds ratio 1.25) and schizophrenia (odds ratio 1.24) predicted needing multiple medications. No genetic scores predicted antidepressant response in the full sample. Monotherapy durations averaged 284 days for benzodiazepines, 204 days for antihistamines, 1,021 days for antidepressants, and 1,744 days for multiple medications.
Limitations
Treatment response was defined by prescription patterns rather than clinical symptom assessments. Prescription data covered only 2005-2018, potentially missing earlier treatments. The study couldn’t distinguish whether multiple-medication patients had more severe initial symptoms or treatment failure. Participants were categorized by prescription text symptoms rather than formal diagnoses. Genetic risk scores explained only modest response variation. Most participants were of European ancestry, limiting generalizability.
Funding and Disclosures
This work was supported by Riksbankens Jubileumsfond (Grant No. P20-0125) and the Swedish Research Council (Grant No. 2023-01093). The Swedish Twin Registry receives funding through the Swedish Research Council (Grant No. 2017-00641). Authors reported no conflicts of interest.
Publication Information
Markant A, Tabrizi F, Grönvall H, Speed D, Åhs F. “Association Between Polygenic Risk Scores and Treatment Response to Antidepressants, Benzodiazepines, and Antihistamines in Anxiety and Depression,” was published in Biological Psychiatry: Global Open Science. May 2025; Volume 5: Article 100470. DOI: https://doi.org/10.1016/j.bpsgos.2025.100470.
