A Sex-Dependent Association between Doxycycline Use and Development of Schizophrenia

Background: Doxycycline and minocycline are brain-penetrant tetracycline antibiotics, which recently gained interest because of their immunomodulatory and neuroprotective properties. Observational studies have suggested that exposure to these drugs may decrease the risk to develop schizophrenia, but results are inconsistent. The aim of this study was to investigate the potential association between doxycycline use and later onset of schizophrenia. Design: We used data from 1 647 298 individuals born between 1980 and 2006 available through Danish population registers. 79 078 of those individuals were exposed to doxycycline, defined as redemption of at least 1 prescription. Survival analysis models stratified for sex with time-varying covariates were constructed to assess incidence rate ratios (IRRs) for schizophrenia (ICD-10 code F20.xx), with adjustment for age, calendar year, parental psychiatric status, and educational level. Results: In the non-stratified analysis, there was no association between doxycycline exposure and schizophrenia risk. However, men who redeemed doxycycline had a significantly lower incidence rate for schizophrenia onset compared to men that did not (IRR 0.70; 95% CI 0.57-0.86). By contrast, women had a significantly higher incidence rate for schizophrenia onset, compared to women that did not redeem doxycycline prescriptions (IRR 1.23; 95% CI 1.08, 1.40). The effects were not found for other tetracycline antibiotics (IRR 1.00; 95% CI 0.91, 1.09). Conclusions: Doxycycline exposure is associated with a sex-dependent effect on schizophrenia risk. The next steps are replication of the results in independent well-characterized population cohorts, as well as preclinical studies to investigate sex-specific effects of doxycycline on biological mechanisms implicated in schizophrenia.