Association between doxycycline use and long-term functioning in patients with schizophrenia.

IMPORTANCE AND OBJECTIVE: The brain-penetrant tetracycline antibiotics, minocycline and doxycycline, have been proposed as potential candidate drugs for treatment of schizophrenia, based on preclinical studies and clinical trials. A potential long-term beneficial effect of these antibiotics for schizophrenia patients has not been investigated. This study was designed to determine if redemption of doxycycline prescription in schizophrenia is associated with decreased incidence of disability pension, a proxy for long-term functioning. DESIGN: We performed a population-based cohort study with data from schizophrenia patients available through the Danish registers. Survival analysis models with time-varying covariates were constructed to assess incidence rate ratios (IRR) of disability pension after exposure to doxycycline or a non-brain penetrant tetracycline, defined as at least one filled prescription. The analysis was adjusted for age, sex, calendar year, parental psychiatric status and educational level. RESULTS: We used data from 11,157 individuals with schizophrenia (4,945 female and 6,212 male; average age 22.4 years old, standard deviation (std) 4.50). 718 of these were exposed to brain-penetrant doxycycline, and 1,498 individuals redeemed a prescription of one or more of the non-brain-penetrant tetracyclines. The average years at risk per person in this cohort was 4.9, and 2,901 individuals received disability pension in the follow-up period. There was a significantly lower incidence rate of disability pension in schizophrenia patients who had redeemed doxycycline compared to patients who did not redeem a prescription of any tetracycline antibiotics (Incidence rate ratio (IRR) 0.68; 95 % CI 0.56, 0.83). There was also a significant lower rate of disability pension in schizophrenia patients who redeemed doxycycline compared to individuals who redeemed a prescription of one of the non-brain penetrant tetracycline antibiotics (IRR 0.69 95 % CI 0.55, 0.87). CONCLUSIONS: In this observational study, doxycycline exposure is associated with a reduced incidence of disability pension. These data support further studies on the potential long term neuroprotective effects of doxycycline and level of functioning in schizophrenia patients.

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.

Evaluating the interrelations between the autism polygenic score and psychiatric family history in risk for autism.

Psychiatric family history or a high autism polygenic risk score (PRS) have been separately linked to autism spectrum disorder (ASD) risk. The study aimed to simultaneously consider psychiatric family history and individual autism genetic liability (PRS) in autism risk. We performed a case-control study of all Denmark singleton births, May 1981-December 2005, in Denmark at their first birthday and a known mother. Cases were diagnosed with ASD before 2013 and controls comprised a random sample of 30,000 births without ASD, excluding persons with non-Denmark-born parents, missing ASD PRS, non-European ancestry. Adjusted odds ratios (aOR) were estimated for ASD by PRS decile and by psychiatric history in parents or full siblings (8 mutually-exclusive categories) using logistic regression. Adjusted ASD PRS z-score least-squares means were estimated by psychiatric family history category. ASD risk (11,339 ASD cases; 20,175 controls) from ASD PRS was not substantially altered after accounting for psychiatric family history (e.g., ASD PRS 10th decile aOR: 2.35 (95% CI 2.11-2.63) before vs 2.11 (95% CI 1.91-2.40) after adjustment) nor from psychiatric family history after accounting for ASD PRS (e.g., ASD family history aOR: 6.73 (95% CI 5.89-7.68) before vs 6.32 (95% CI 5.53-7.22) after adjustment). ASD risk from ASD PRS varied slightly by psychiatric family history. While ASD risk from psychiatric family history was not accounted for by ASD PRS and vice versa, risk overlap between the two factors will likely increase as measures of genetic risk improve. The two factors are best viewed as complementary measures of family-based autism risk. LAY SUMMARY: Autism risk from a history of mental disorders in the immediate family was not explained by a measure of individual genetic risk (autism polygenic risk score) and vice versa. That is, genetic risk did not appear to overlap family history risk. As genetic measures for autism improve then the overlap in autism risk from family history versus genetic factors will likely increase, but further study may be needed to fully determine the components of risk and how they are inter-related between these key family factors. Meanwhile, the two factors may be best viewed as complementary measures of autism family-based risk.

Mental and pediatric disorders among children 0-6 years of parents with severe mental illness.

OBJECTIVE: Parental severe mental illness (SMI) increases the lifetime risk of mental and pediatric disorders in the offspring but little is known about specific disorders during early childhood. The primary aim was to investigate the incidence of mental and pediatric disorders among children 0-6 years old exposed to parental SMI, and secondarily to investigate the distribution of disorders on specific child age. METHODS: A nationwide, register-based cohort study of 1,477,185 children born in Denmark between 1994.01.01 and 2016.12.31. Incidence rate ratios were calculated using Poisson regression analysis for any and specific mental and pediatric disorders. RESULTS: IRR for any psychiatric disorder was elevated by a factor 2-5 among SMI offspring. Maternal schizophrenia resulted in the highest IRR = 5.23 (4.80-5.69) of any child psychiatric disorder. The risk of anxiety/OCD and attachment disorder among offspring exposed to parental, and in particular maternal, SMI was markedly raised with IRRs for anxiety/OCD between 7.59 and 17.02 and attachment disorders between 6.26 and 15.40. IRRs of mental disorders were highest at age 0-1 year and declined with age. IRR for any pediatric disorder was also elevated with IRRs between 1.01 and 1.28. Disorders of the digestive system and ill-defined symptoms were associated with the highest IRRs. Maternal (vs. paternal) SMI was associated with higher IRRs. IRRs declined slightly with child age. CONCLUSION: Children exposed to parental SMI are at increased risk of mental and pediatric disorders during early childhood, particularly anxiety/OCD and attachment disorders. If associations are estimates of a modifiable causal relationship, our results indicate a need for early intervention to promote mental and pediatric health among SMI offspring.

School performance of children whose parents suffered torture and war-a register-based study in Denmark.

BACKGROUND: Young refugees and descendants of refugees have different preconditions for learning than their peers without refugee background. Children growing up in families where parents have suffered torture and war trauma may represent a particularly vulnerable group. This study investigates whether children of torture survivors living in Denmark achieved different test scores throughout primary and secondary school compared to children of non-traumatized parents. METHODS: Using data from a national school test programme, tests from Grades 2-8 were compared for children whose parents had been treated for torture and war trauma as to their peers. Referral to specialized rehabilitation clinics was used to identify the traumatized parent group. The mean score difference was estimated using multilevel linear regression, and outcomes were measured within groups of parental region of origin to allow for region-specific effects. The odds of missing a test were also estimated with multilevel logistic regression. RESULTS: The study included 854 467 children [median age (interquartile range) =12 (3.3)] of which 7809 were children of the trauma-exposed parents. The analysis revealed that children of torture survivors achieved test scores between -6% (95% CI: -0.13, 0.00) and -38% (95% CI: -0.44, -0.32) of a standard deviation compared to children of non-traumatized parents, adjusted for the main effect of region of origin. They were also more likely to miss a test [OR=4.95 (95% CI: 4.30, 5.71)]. CONCLUSIONS: The findings indicate that risk factors for poorer school performance cluster in children of traumatized refugee parents, and reveal the possible adverse educational effects of trauma across generations.

Excess mortality in persons with severe mental disorders: a multilevel intervention framework and priorities for clinical practice, policy and research agendas.

Excess mortality in persons with severe mental disorders (SMD) is a major public health challenge that warrants action. The number and scope of truly tested interventions in this area remain limited, and strategies for implementation and scaling up of programmes with a strong evidence base are scarce. Furthermore, the majority of available interventions focus on a single or an otherwise limited number of risk factors. Here we present a multilevel model highlighting risk factors for excess mortality in persons with SMD at the individual, health system and socio-environmental levels. Informed by that model, we describe a comprehensive framework that may be useful for designing, implementing and evaluating interventions and programmes to reduce excess mortality in persons with SMD. This framework includes individual-focused, health system-focused, and community level and policy-focused interventions. Incorporating lessons learned from the multilevel model of risk and the comprehensive intervention framework, we identify priorities for clinical practice, policy and research agendas.

Children of Parents With Serious Mental Illness: With Whom Do They Grow Up? A Prospective, Population-Based Study.

OBJECTIVE: To provide an overview of living arrangements during childhood for children of parents with schizophrenia, bipolar disorder, and depression. METHOD: Information was obtained from Danish registers on children's addresses and used to calculate the proportion living in different household living arrangements. The study was conducted as a prospective, register-based cohort study covering all children in the entire Danish population born after 1982 (N = 1,823,625) and their parents with a diagnosis of schizophrenia, bipolar disorder, depression, or none of these disorders. Regression analyses were performed assessing the risk of dissolution of the conjugal family. RESULTS: Children's living arrangements were characterized by fewer nuclear families and more single-parent-headed households when parents had serious mental illness (SMI). From birth, 15% to 20% of children lived with a single mother with SMI. Conjugal families were dissolved at higher rates if a parent had SMI, especially if the mother (incidence rate ratio 2.98; 95% CI 2.80-3.17) or the father (incidence rate ratio 2.60; 95% CI 2.47-2.74) had schizophrenia. Risks for family dissolution varied greatly with parents' socioeconomic position in all diagnostic groups. CONCLUSION: Parents' SMI affects children's family living arrangements because fewer children live with both parents and more children live with a single parent or are separated from both parents. Family cohesion seems especially difficult to maintain when parents have schizophrenia.

Serious mental illness and disrupted caregiving for children: a nationwide, register-based cohort study.

OBJECTIVE: To study how often severe psychiatric disorders adversely affect a person's ability to be a parent, indicated by the child being placed in out-of-home care. METHOD: This study was conducted in 2013 as a prospective, register-based cohort study covering all first-born singletons in the entire Danish population born after 1982 (N = 782,092) and their parents. Rates of out-of-home placement of children with parents diagnosed with schizophrenia, bipolar disorder, or unipolar depression, according to the criteria of the International Statistical Classification of Diseases and Related Health Problems, 8th revision (ICD-8) and ICD, 10th revision (ICD-10), were analyzed. The rates were compared with those of children with parents from the general population. RESULTS: A parental diagnosis of schizophrenia was the most prominent risk factor for children placed outside the home, with an accumulated risk for being placed in care at some point during childhood-40% for children with mothers with schizophrenia and 20% for children with fathers with schizophrenia. Children of mothers (incidence rate ratio [IRR] = 23.75; 95% CI, 20.94-26.93) and fathers (IRR = 7.85; 95% CI, 6.67-9.25) with a diagnosis of schizophrenia had the overall highest IRRs of placement in care. Having a mother with bipolar disorder was the second most prominent risk factor (IRR = 5.76; 95% CI, 4.50-7.36), followed by a maternal diagnosis of unipolar depression (IRR = 4.28; 95% CI, 3.73-4.90). Risks were especially high during the child's first year of life, indicating a critical period, especially for children with mothers with schizophrenia (IRR = 80.19; 95% CI, 68.09-94.43). Risks varied greatly with parents' socioeconomic factors in all diagnostic groups. CONCLUSIONS: Parental schizophrenia is a strong risk factor for placement of children in out-of-home care.

Schizophrenia and the risk for breast cancer.

The authors investigated the risk for breast cancer in schizophrenia in a cohort of 1336313 Danish women born after 1935, including information on reproductive factors. In all, 7541 had been hospitalized for schizophrenia in 1970-1997 and the overall relative risk for breast cancer adjusted for age, period, age at first birth and number of births was not increased (RR, 0.91; 95% confidence interval, 0.71-1.12). Studies not taking parity into account may overestimate the risk for breast cancer in schizophrenic women.