Doxycycline, a broad-spectrum antibiotic commonly used to treat infections and acne, may help reduce the risk for schizophrenia in high-risk adolescents, new research suggests.

A Finnish registry study showed that adolescents who had received psychiatric health services and were treated with doxycycline had about a 30-35% lower risk of developing schizophrenia in adulthood compared with peers treated with other antibiotics.

The study raises the “tentative but exciting” possibility that doxycycline treatment may reduce schizophrenia risk in adolescent psychiatric patients, wrote the researchers, led by Ian Kelleher, MD, PhD, professor of child and adolescent psychiatry, University of Edinburgh, Edinburgh, Scotland.

“Because the study was observational in nature and not a randomized controlled trial, it means we can’t draw firm conclusions on causality,” Kelleher said in a press release. “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.”

The study was published online on November 5 in the American Journal of Psychiatry.

Emulated Target Trial Design

Previous studies have offered conflicting results on the link between doxycycline and psychosis risk. While some research suggests the antibiotic isn’t an effective treatment for existing psychotic disorders, investigators noted that there is some evidence that doxycycline may improve long-term functioning in schizophrenia.

To examine whether doxycycline may have a preventive effect, Kelleher and colleagues applied a target trial emulation design to a population-wide dataset to test whether doxycycline, an antibiotic with putative neuroprotective properties, might protect against schizophrenia in high-risk adolescents.

Using Finnish health records, they identified 56,395 individuals who attended inpatient or outpatient psychiatric services between ages 13 years and 18 years and had been prescribed antibiotics. Of these, 16,189 (29%) had been treated with doxycycline.

Those given doxycycline were older when they entered follow-up (mean age, 18.8 years vs 15.4 years), were more likely to be women and had different psychiatric diagnoses.

“If this were a typical observational study, these would be important potential confounds,” Kelleher told Medscape Medical News.

“The strength of this study, however, was that it involved a target trial emulation framework, using methods specifically designed to address those differences...and distill the estimate down to the likely effect of the medication itself,” Kelleher explained.

At 10 years, the risk for schizophrenia was 2.1% for individuals who had received nondoxycycline antibiotics.

In comparison, the risk for schizophrenia at 10 years with doxycycline use was 1.4% (risk ratio [RR], 0.65) in the low (< 1499 mg cumulative dose) and medium (1500-299 mg cumulative dose) use groups and 1.5% (RR, 0.70) in the high use group (≥ 3000 mg).

The results were similar when looking at risk at 15 years and were consistent across both outpatient and inpatient adolescent psychiatric samples.

A Role for Inflammation?

It’s been hypothesized that doxycycline’s potential protective effect on schizophrenia may be due to its ability to reduce inflammation and influence synaptic pruning.

“Interestingly, research from animal labs shows that, even at low doses, doxycycline can have long-term effects on ‘learned immunity,’ reducing activation of microglia, which are the brain’s resident macrophages and which are responsible for synaptic pruning — the normal process by which brain cell connections are ‘pruned’ or sheared,” Kelleher told Medscape Medical News.

“There appears to be excessive synaptic pruning in people who develop schizophrenia — that could be how doxycycline works to reduce schizophrenia risk, by dampening down microglia activity in the brain. We’ll need further research to figure out if that’s the case,” Kelleher said.

The evidence of an upregulated inflammatory status and immune dysfunction has long been described in patients with schizophrenia, said Xiaoduo Fan, MD, MPH, professor of psychiatry, UMass Chan Medical School, Worcester, Massachusetts, and director of UMass MIND, who was not part of the new study.

For example, studies from Fan’s group have found abnormal patterns of immune activation, including elevated serum levels of interleukin (IL)-1 beta, IL-6, and TNF-alpha in patients with first-episode schizophrenia.

“The findings from our group also suggest that the dysregulation of inflammatory and immunological processes is likely related to the manifestation of symptoms and treatment response of schizophrenia,” Fan told Medscape Medical News.

For example, his team found that elevated levels of specific inflammatory biomarkers, including C-reactive protein and white blood cell count, were associated with negative symptoms of schizophrenia. Further, in a 12-week, randomized, double-blind, placebo-controlled study, they showed that adjunctive treatment with telmisartan, an angiotensin II receptor blocker with anti-inflammatory properties, significantly improved overall symptoms of schizophrenia.

And in a 16-week, randomized, double-blind, placebo-controlled study, his team showed that adjunctive minocycline treatment improved negative symptoms of schizophrenia.

Causal Link Not Established

Findings from the new trial provide “indirect, real-world evidence that doxycycline may reduce the risk of developing schizophrenia in adolescent psychiatric patients,” Fan said.

“The findings are an addition to the existing literature that suggests potential treatment benefits of broad-spectrum antibiotics, including doxycycline and minocycline, in individuals with established schizophrenia,” said Fan.

“However, given the various limitations the authors noted in the paper, a causal relationship between doxycycline treatment and reduced schizophrenia risk cannot be drawn from this study,” said Fan.

David Curtis, MBBS, MD, PhD, with University College London Genetics Institute, London, England, echoed that sentiment in a statement from the UK nonprofit Science Media Centre.

“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,” Curtis commented.

“From everything we know, I find it quite hard to believe that prescription of doxycycline would reduce the risk of developing schizophrenia,” Curtis added.

This study had no commercial funding. Kelleher, Curtis, and Fan had no relevant disclosures.