Abstract
Doxycycline has been hypothesized to prevent development of severe mental illness (SMI) through the suppression of microglia, especially if administered during the intense synaptic pruning period of adolescence. However, results from register studies on potential benefits differ considerably. The aim of the present study was to determine whether doxycycline exposure during adolescence is associated with reduced SMI risk, and to investigate if a direct and specific causality is plausible. This is a Swedish national population register-based cohort study of all individuals born from 1993 to 1997, followed from the age of 13 until end of study at the end of 2016. The primary exposure was cumulative doxycycline prescription ≥3000 mg and outcomes were first diagnosis of non-affective psychosis (F20–F29) and first diagnosis of bipolar disorder (F30–F31). Causal effects were explored through Cox regressions with relevant covariates and secondary analyses of multilevel exposure and comparison to other antibiotics. We found no association between doxycycline exposure and risk of subsequent non-affective psychosis (adjusted hazard ratio (HR) 1.15, 95% CI 0.73–1.81, p = 0.541) and an increased risk of subsequent bipolar disorder (adjusted HR 1.95, 95% CI 1.49–2.55, p < 0.001). We do not believe the association between doxycycline and bipolar disorder is causal as similar associations were observed for other common antibiotics.
Highlights
Severe mental illness (SMI) often results in lifelong and extensive consequences for individuals and society, whereof most evident is a reduced life expectancy in the magnitude of decades [1,2,3,4,5]
Results from several lines of research support the hypothesis that excessive activity in the removal of synapses by microglia that normally occurs during adolescence contributes to the onset of schizophrenia in early adulthood [13,14,15,16,17,18]
A somewhat attenuated association was observed from the regression stratified by sex and adjusted for covariates (HR 1.65, 95% CI 1.51–1.81, p < 0.001)
Summary
Severe mental illness (SMI) often results in lifelong and extensive consequences for individuals and society, whereof most evident is a reduced life expectancy in the magnitude of decades [1,2,3,4,5]. Sellgren et al added analyses of 22,027 electronic health records from two large US medical centers and found an inverse association (HR 0.58, 95% confidence interval (CI) 0.39–0.88) between minocycline and/or doxycycline exposure during adolescence for a minimum of 90 days (3811 individuals) and risk of later diagnosis of nonaffective psychosis, including schizophrenia (F20–F29) [24] This contrasts an earlier electronic healthcare register study from UK by Herrero-Zazo et al who compared 13,248 minocycline exposed for a minimum of 42 days with 14,393 matched controls and found no preventive effect on SMI from early minocycline prescription [25]. If a typical dosage of 100 mg/day is used for conversion, the Sellgren et al threshold would roughly translate to a total exposure of ≥9000 mg and the Herrero-Zazo et al to ≥4200 mg
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