Doxycycline Use in Adolescent Psychiatric Patients and Risk of Schizophrenia: An Emulated Target Trial

As many as half of individuals who develop psychosis had attended child and adolescent psychiatric services at some stage in childhood, highlighting substantial opportunities for prevention within these services if an effective preventive intervention were identified. The authors hypothesized that adolescent psychiatric patients exposed to doxycycline, an antibiotic with putative neuroprotective properties, would have a lower risk of developing schizophrenia.

This was an emulated target trial using nationwide Finnish health register data on all individuals born between 1987 and 1997 who attended adolescent psychiatric services between ages 13 and 18 and had used any antibiotics. Individuals were followed from first dispensed antibiotic prescription up to age 30. The main outcome was recorded schizophrenia diagnosis. The g-formula was used to estimate schizophrenia risk across doxycycline exposure levels (cumulative dose doxycycline use: no doxycycline use; low use, <1,499 mg; medium use, 1,500-2,999 mg; high use, ≥3,000 mg) during different follow-up periods.

A total of 56,395 individuals had attended adolescent psychiatric services and had used antibiotics; of these, 16,189 (28.7%) had used doxycycline. The risk of schizophrenia after 10 years of follow-up was 2.1% (95% CI=1.9, 2.3) for individuals who had used non-doxycycline antibiotics. In comparison, the risk of schizophrenia at 10 years was significantly lower in adolescent psychiatric patients treated with doxycycline (low cumulative dose: 1.4%, risk ratio=0.70, 95% CI=0.48, 0.85; medium cumulative dose: 1.4%, risk ratio=0.65, 95% CI=0.25, 1.04; high cumulative dose: 1.5%, risk ratio=0.70, 95% CI=0.43, 0.97).

These findings raise the tentative but exciting possibility that doxycycline treatment may reduce schizophrenia risk in adolescent psychiatric patients.