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A commonly prescribed antibiotic used to treat skin conditions and infections may offer protection against the development of schizophrenia. New research published in the American Journal of Psychiatry suggests that adolescents in psychiatric care who took doxycycline had a lower risk of developing the disorder later in adulthood compared to those who took other antibiotics. This finding provides a potential lead for preventing a severe mental illness that currently lacks proven preventive interventions.
Schizophrenia is one of the most disabling medical conditions in existence. It impacts an individual’s physical health as well as their social, educational, and occupational life. Medical experts have sought effective ways to prevent the onset of psychosis for decades. Identifying interventions for high-risk individuals remains a primary ambition for the field of psychiatry.
Current data indicates that the peak onset of psychotic disorders occurs after the age of 20. However, a substantial number of people who eventually receive a diagnosis interact with child and adolescent mental health services years earlier. Research from Finland has shown that nearly half of all people diagnosed with psychotic disorders had attended adolescent psychiatric clinics. This widespread early contact suggests that these clinics could serve as a venue for early intervention if effective preventive treatments existed.
The biological mechanisms underlying schizophrenia are not fully understood, but inflammation and synaptic issues are leading theories. Scientists believe that a process called synaptic pruning plays a central role in the development of the disorder. Synaptic pruning is a natural developmental stage where the brain eliminates weak or unnecessary neural connections. In schizophrenia, this process may become excessive and result in the loss of too many connections.
Doxycycline is a broad-spectrum antibiotic widely used to treat acne vulgaris and various infections. Beyond its antibacterial properties, the drug is known to enter the brain easily. It has demonstrated neuroprotective effects in laboratory models of nervous system disorders. Previous experiments suggest that doxycycline might inhibit the immune cells responsible for excessive synaptic pruning.
A team of researchers led by Ian Kelleher at the University of Edinburgh and colleagues from the Finnish Institute for Health and Welfare investigated whether this drug could reduce schizophrenia risk in humans. They hypothesized that the drug’s anti-inflammatory and neuroprotective properties might interrupt the biological pathway toward psychosis.
To test this, they utilized a massive dataset from the Finnish health registry. The study population included all individuals born in Finland between 1987 and 1997 who had attended adolescent psychiatric services between ages 13 and 18.
The investigators employed a method known as an emulated target trial. This statistical approach attempts to mimic the rigorous design of a randomized controlled trial using existing observational data. It allows researchers to establish strict criteria for who is included in the “treatment” and “control” groups. This method helps to reduce some of the biases that typically affect observational studies.
The study focused on young people who had received a prescription for antibiotics. The researchers compared those who were prescribed doxycycline against those who were prescribed other types of antibiotics. This active comparison group helped account for the possibility that having an infection itself might influence mental health outcomes. The total sample consisted of 56,395 individuals.
Of this group, roughly 29 percent received prescriptions for doxycycline. The researchers tracked these individuals from their first antibiotic prescription until they reached age 30, died, or moved out of the country. The primary outcome they looked for was a recorded diagnosis of schizophrenia. The team adjusted their statistical models to account for variables such as sex, birth year, and parental education.
The analysis revealed a significant difference in outcomes between the two groups. Among patients who took antibiotics other than doxycycline, the estimated risk of developing schizophrenia within ten years was 2.1 percent. In contrast, those who took doxycycline showed a significantly lower risk. For these individuals, the ten-year risk dropped to approximately 1.4 percent.
This represents a relative risk reduction of roughly 33 percent. The protective association was evident across different levels of cumulative exposure to the drug. Even individuals who took relatively low cumulative doses appeared to benefit from this reduction in risk. The researchers calculated the “number needed to treat” to prevent one case of schizophrenia. They estimated that for every 132 to 160 adolescents treated with doxycycline, one case of schizophrenia might be prevented.
The study also examined a subgroup of patients who had more severe mental health needs during adolescence. This included individuals who had been admitted to a psychiatric hospital as teenagers. The results for this high-risk group were consistent with the broader findings. Doxycycline use was associated with a roughly 40 to 50 percent reduction in the risk of schizophrenia compared to the use of other antibiotics in this inpatient population.
The researchers investigated whether the reduction in risk applied to other types of psychotic disorders. They found that the association was specific to schizophrenia. Doxycycline use did not appear to significantly lower the risk of developing broader nonaffective psychotic disorders. This distinction may be due to the specific biological pathways involving inflammation that are more prominent in schizophrenia than in other psychoses.
The team also conducted several sensitivity analyses to test the robustness of their findings. They checked whether the link could be explained by the fact that doxycycline is often used for acne. They analyzed whether acne medication in general was linked to lower psychosis risk and found it was not. This suggests that the benefit is likely linked to the specific properties of doxycycline rather than the condition it treats.
Professor Ian Kelleher, the study lead, commented on the implications of the work. He stated, “As many as half of the people who develop schizophrenia had previously attended child and adolescent mental health services for other mental health problems. At present, though, we don’t have any interventions that are known to reduce the risk of going on to develop schizophrenia in these young people. That makes these findings exciting.”
Despite the promising results, the study has limitations inherent to its design. Because it was observational, it cannot definitively prove that doxycycline caused the reduction in schizophrenia cases. The researchers could not control for all possible differences between the groups. For instance, the group prescribed doxycycline was older on average and included more females than the comparison group.
Kelleher addressed the limitations regarding causality. He explained, “Because the study was observational in nature and not a randomized controlled trial, it means we can’t draw firm conclusions on causality, but this is an important signal to further investigate the protective effect of doxycycline and other anti-inflammatory treatments in adolescent psychiatry patients as a way to potentially reduce the risk of developing severe mental illness in adulthood.”
Experts not involved in the study provided additional context. Katharina Schmack from The Francis Crick Institute highlighted the significance of the study population. She told the Science Media Centre, “This is the first study to look at the link between doxycycline and schizophrenia risk in health records of adolescents seeking mental health care. This is an important population to study as these adolescents already face an elevated risk for schizophrenia.”
However, Schmack also pointed out the modest absolute numbers. She explained, “And while the effects observed here are statistically significant, the absolute numbers are modest: at 15 years, doxycycline treatment at the highest dose was associated with a reduction of approximately 2.5% of absolute risk, meaning that instead of about 5 out of 100 people now roughly 2-3 out of 100 would develop schizophrenia.”
Dominic Oliver of the University of Oxford discussed the biological plausibility of the findings. He referenced the drug’s ability to cross the blood-brain barrier and its anti-inflammatory effects. He said, “Overall, this is an important study that opens the door to new avenues for preventive treatments for psychosis. Confirming these findings in other large datasets (and eventually in randomised controlled trials) is essential before doxycycline can be considered for preventive use in young people at risk of psychosis.”
Others remained more skeptical about the ability to rule out confounding factors. David Curtis of University College London noted the demographic differences between the two antibiotic groups. He stated, “The main problem with this study is that, by recruiting people at the time that they were prescribed doxycycline or a different antibiotic, the researchers ended up with two groups which clearly differ in a number of important ways.”
Curtis continued by expressing doubt about the causal link. He remarked, “Given the fact that there are marked differences between the two groups, even if we attempt to account for known confounders there’s really no way to tell that any difference in risk of developing schizophrenia is due to the doxycycline treatment or for some other reason. From everything we know, I find it quite hard to believe that prescription of doxycycline would reduce the risk of developing schizophrenia.”
The authors acknowledge that a randomized controlled trial would be the ideal way to confirm these results. Such a trial would be challenging to conduct due to the long timeframe required for schizophrenia to develop. It would require following a large number of participants for many years. They note that while the findings are exciting, they are preliminary. Confirmatory research is necessary before any changes to clinical practice can be recommended. Future studies should aim to replicate these findings in different populations.
The study, “Doxycycline Use in Adolescent Psychiatric Patients and Risk of Schizophrenia: An Emulated Target Trial,” was authored by Ulla Lång, Johanna Metsälä, Hugh Ramsay, Fiona Boland, Katriina Heikkilä, Anna Pulakka, Anne Lawlor, Karen O’Connor, Juha Veijola, Eero Kajantie, Colm Healy, and Ian Kelleher.
