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Poster #95 HEAD INJURY AND INFLAMMATORY REACTIONS AS RISK FACTORS FOR PSYCHIATRIC DISORDERS: A NATIONWIDE REGISTER-BASED STUDY
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
Discussion: This study provides evidence suggesting that severe physical abuse from either parent in childhood is a significant predictor for suicidal behaviourat the time of the first presentation to mental health services. However, the other childhood traumas such as severe sexual abuse, antipathy from parent and neglect from either parent were not significant predictors for future self harm behaviours. Understanding the nature of any link between childhood adversity and suicidal behaviour will have important implications both for prevention and intervention.
Poster #93 CARDIOVASCULAR DRUG USE IN PATIENTS WITH SCHIZOPHRENIA OR BIPOLAR DISORDER Thomas M. Laursen 1 , Preben B. Mortensen 1 , James H. MacCabe 2 , Dan Cohen 3 , Christiane Gasse 1 1 Aarhus University, Aarhus, Denmark; 2 Department of Psychosis Studies, Institute of Psychiatry, London, United Kingdom; 3 Mental Health Organization North-Holland North, Heerhugowaard, Netherlands Background: Cardiovascular comorbidity is one of the major modifiable risk factors driving the excess mortality in individuals with schizophrenia or bipolar disorder. Population-based studies in this area are sparse.We aimed at examining the incidence of drugs used in cardiovascular disease (CVD drugs) in subjects with schizophrenia or bipolar disorder compared with the general population and its impact on mortality. Methods: A register-based population-based cohort study based on the Danish population between 1995 and 2008 using data on dispensing for CVD drugs was conducted. Using Poisson regression analysis, we calculated incidence rate ratios (IRRs) for CVD drug use, and mortality rate ratios (MRRs), adjusted for gender, age, calendar time, and Charlson Index (an index of the degree of somatic disorders) comparing individuals with schizophrenia or bipolar disorder with subjects with no prior psychiatric hospitalization. Results: Compared with persons with no prior psychiatric hospitalization, IRRs for most CVD drugs were significantly decreased in persons with schizophrenia or bipolar disorder, e.g. IRRs for lipid modifying agents; schizophrenia 0.84 (0.77 – 0.93), bipolar disorder 0.87 (0.77 – 0.97). In contrast the overall mortality was higher for individuals with schizophrenia (MRR=3.96) and bipolar disorder (MRR=1.97). However, contrary to our hypothesis, CVD drug use was associated with reduced excess mortality from unnatural causes, but not reduced excess cardiovascular mortality. Discussion: The present study shows an apparent deficit in the use of most CVD drugs among persons with schizophrenia or bipolar disorder compared to the general population in Denmark. A causative link between the deficit in cardiovascular care and the high mortality in schizophrenic and bipolar patients is not fully established, however, our findings are suggestive of such a relation.
Poster #94 INFLAMMATORY MARKERS IN NEONATES AND SCHIZOPHRENIA IN ADOLESCENCE AND EARLY ADULTHOOD: A STUDY USING THE DANISH PKU BIOBANK AND NATIONAL REGISTERS Philip R. Nielsen 1 , Nanna Larsen 2 , Kristin Skogstrand 2 , David M. Hougaard 2 , Preben B. Mortensen 1 1 Aarhus University, Aarhus, Denmark; 2 Statens Serum Institut, Copenhagen, Denmark Background: An extensive literature has described that increased risk for schizophrenia is associated with a wide variety of different infectious agents. It has been come increasingly clear, however, that many of the infections studied in relation to schizophrenia may act by indirect mechanisms. One of the most widely studied mechanisms involves the release of cytokines in response to infectious insults. The literature concerning these animal studies have recently been extensively reviewed. Cytokines are important not only for behavioral changes during acute illness, but may also underlie long-term changes in behavior as a consequence of a neurodevelopmental disturbance early in life. As little is known about cytokines in early neonatal life and their influence on developing schizophrenia, the possibility of measuring a broad panel of inflammatory cytokines and neu-
S219
rotrophic markers in small amount of blood available in archived newborn dried blood spot samples is therefore of great interest to the study of schizophrenia. Methods: We therefore utilized the National Danish Neonatal Screening Biobank including approximately 2 million individuals born in Denmark since May 1, 1981. Using population-based Danish registers, we identified individuals with a diagnosis of schizophrenia and matched those to controls of same sex and day-of-birth. In the present study we have investigated the possible association between schizophrenia and endogenous inflammatory markers in dried blood spot samples (DBSS). A panel of inflammatory markers was measured by a previously validated multiplex sandwich immunoassay based on the Luminex xMAP technology. Results: Our preliminary data suggest that elevated pro-inflammatory cytokine levels are associated with schizophrenia risk, replication data from an expanded sample will be presented Discussion:
Poster #95 HEAD INJURY AND INFLAMMATORY REACTIONS AS RISK FACTORS FOR PSYCHIATRIC DISORDERS: A NATIONWIDE REGISTER-BASED STUDY Sonja Orlovska 1 , Michael E. Benros 1,2 , Preben B. Mortensen 2 , Merete Nordentoft 1 1 University of Copenhagen Copenhagen, Copenhagen, Denmark; 2 University of Aarhus Aarhus, Aarhus, Denmark Background: Head injury has been associated with psychiatric disorders for decades but studies investigating the possibility of a causal relationship have produced conflicting results and are often hampered by methodological problems. Head injury has been shown to elicit a potentially harmful inflammatory reaction in the brain. Moreover, it has been suggested that head injury increases the permeability of the blood-brain barrier (BBB) with a subsequent traumatic release of central nervous system (CNS) antigens into the peripheral blood. The CNS antigens are unknown to the immune system which could induce reactivity against brain tissue. Since infections are also shown to increase the permeability of the BBB, a subsequent infection might increase the risk of an inflammatory and detrimental reaction against brain tissue. In this study we investigate whether head injury increases the risk of psychiatric disorders and the possible effect of subsequent infections. Methods: The study is based on the linkage between nationwide population-based registers in Denmark, including the Danish National Hospital Registry and the Danish Psychiatric Central Register. This allows us to study whether the diagnoses of schizophrenia spectrum disorders, bipolar disorder, unipolar depression and organic mental disorders appear more frequently in persons exposed to head injury and the possible effect of subsequent infections. Individuals with a diagnosis of epilepsy or any mental disorder before exposure will be excluded and, among other confounders, we will adjust for place of birth and a family history of psychiatric disorders. An additional analysis performed in a case-sibling design will give an adjustment of several socioeconomic aspects in an indirect manner. The analyses will be based on data ranging from 1 January 1977 to 31 December 2010 which gives a period of more than three decades. Data will be analyzed using survival analysis techniques and the incidence rate ratios (IRRs) are used as an approximation of the relative risk estimated by Poisson regression. Results: Results will be ready for presentation at the conference. Discussion: The present population-based cohort study will be the largest study so far and be the first to consider whether inflammation plays a part in the relationship between head injury and psychiatric disorders. We will exclude persons diagnosed with epilepsy and include the diagnoses of organic mental disorders as outcome – aspects that have rarely been taken into consideration in previous studies. Furthermore, we will include a combined group of fractures not involving the skull or spine as a comparison group in order to estimate if the results are due to increased risk behaviour in not yet diagnosed psychiatric patients.
Discussion: This study provides evidence suggesting that severe physical abuse from either parent in childhood is a significant predictor for suicidal behaviourat the time of the first presentation to mental health services. However, the other childhood traumas such as severe sexual abuse, antipathy from parent and neglect from either parent were not significant predictors for future self harm behaviours. Understanding the nature of any link between childhood adversity and suicidal behaviour will have important implications both for prevention and intervention.
Poster #93 CARDIOVASCULAR DRUG USE IN PATIENTS WITH SCHIZOPHRENIA OR BIPOLAR DISORDER Thomas M. Laursen 1 , Preben B. Mortensen 1 , James H. MacCabe 2 , Dan Cohen 3 , Christiane Gasse 1 1 Aarhus University, Aarhus, Denmark; 2 Department of Psychosis Studies, Institute of Psychiatry, London, United Kingdom; 3 Mental Health Organization North-Holland North, Heerhugowaard, Netherlands Background: Cardiovascular comorbidity is one of the major modifiable risk factors driving the excess mortality in individuals with schizophrenia or bipolar disorder. Population-based studies in this area are sparse.We aimed at examining the incidence of drugs used in cardiovascular disease (CVD drugs) in subjects with schizophrenia or bipolar disorder compared with the general population and its impact on mortality. Methods: A register-based population-based cohort study based on the Danish population between 1995 and 2008 using data on dispensing for CVD drugs was conducted. Using Poisson regression analysis, we calculated incidence rate ratios (IRRs) for CVD drug use, and mortality rate ratios (MRRs), adjusted for gender, age, calendar time, and Charlson Index (an index of the degree of somatic disorders) comparing individuals with schizophrenia or bipolar disorder with subjects with no prior psychiatric hospitalization. Results: Compared with persons with no prior psychiatric hospitalization, IRRs for most CVD drugs were significantly decreased in persons with schizophrenia or bipolar disorder, e.g. IRRs for lipid modifying agents; schizophrenia 0.84 (0.77 – 0.93), bipolar disorder 0.87 (0.77 – 0.97). In contrast the overall mortality was higher for individuals with schizophrenia (MRR=3.96) and bipolar disorder (MRR=1.97). However, contrary to our hypothesis, CVD drug use was associated with reduced excess mortality from unnatural causes, but not reduced excess cardiovascular mortality. Discussion: The present study shows an apparent deficit in the use of most CVD drugs among persons with schizophrenia or bipolar disorder compared to the general population in Denmark. A causative link between the deficit in cardiovascular care and the high mortality in schizophrenic and bipolar patients is not fully established, however, our findings are suggestive of such a relation.
Poster #94 INFLAMMATORY MARKERS IN NEONATES AND SCHIZOPHRENIA IN ADOLESCENCE AND EARLY ADULTHOOD: A STUDY USING THE DANISH PKU BIOBANK AND NATIONAL REGISTERS Philip R. Nielsen 1 , Nanna Larsen 2 , Kristin Skogstrand 2 , David M. Hougaard 2 , Preben B. Mortensen 1 1 Aarhus University, Aarhus, Denmark; 2 Statens Serum Institut, Copenhagen, Denmark Background: An extensive literature has described that increased risk for schizophrenia is associated with a wide variety of different infectious agents. It has been come increasingly clear, however, that many of the infections studied in relation to schizophrenia may act by indirect mechanisms. One of the most widely studied mechanisms involves the release of cytokines in response to infectious insults. The literature concerning these animal studies have recently been extensively reviewed. Cytokines are important not only for behavioral changes during acute illness, but may also underlie long-term changes in behavior as a consequence of a neurodevelopmental disturbance early in life. As little is known about cytokines in early neonatal life and their influence on developing schizophrenia, the possibility of measuring a broad panel of inflammatory cytokines and neu-
S219
rotrophic markers in small amount of blood available in archived newborn dried blood spot samples is therefore of great interest to the study of schizophrenia. Methods: We therefore utilized the National Danish Neonatal Screening Biobank including approximately 2 million individuals born in Denmark since May 1, 1981. Using population-based Danish registers, we identified individuals with a diagnosis of schizophrenia and matched those to controls of same sex and day-of-birth. In the present study we have investigated the possible association between schizophrenia and endogenous inflammatory markers in dried blood spot samples (DBSS). A panel of inflammatory markers was measured by a previously validated multiplex sandwich immunoassay based on the Luminex xMAP technology. Results: Our preliminary data suggest that elevated pro-inflammatory cytokine levels are associated with schizophrenia risk, replication data from an expanded sample will be presented Discussion:
Poster #95 HEAD INJURY AND INFLAMMATORY REACTIONS AS RISK FACTORS FOR PSYCHIATRIC DISORDERS: A NATIONWIDE REGISTER-BASED STUDY Sonja Orlovska 1 , Michael E. Benros 1,2 , Preben B. Mortensen 2 , Merete Nordentoft 1 1 University of Copenhagen Copenhagen, Copenhagen, Denmark; 2 University of Aarhus Aarhus, Aarhus, Denmark Background: Head injury has been associated with psychiatric disorders for decades but studies investigating the possibility of a causal relationship have produced conflicting results and are often hampered by methodological problems. Head injury has been shown to elicit a potentially harmful inflammatory reaction in the brain. Moreover, it has been suggested that head injury increases the permeability of the blood-brain barrier (BBB) with a subsequent traumatic release of central nervous system (CNS) antigens into the peripheral blood. The CNS antigens are unknown to the immune system which could induce reactivity against brain tissue. Since infections are also shown to increase the permeability of the BBB, a subsequent infection might increase the risk of an inflammatory and detrimental reaction against brain tissue. In this study we investigate whether head injury increases the risk of psychiatric disorders and the possible effect of subsequent infections. Methods: The study is based on the linkage between nationwide population-based registers in Denmark, including the Danish National Hospital Registry and the Danish Psychiatric Central Register. This allows us to study whether the diagnoses of schizophrenia spectrum disorders, bipolar disorder, unipolar depression and organic mental disorders appear more frequently in persons exposed to head injury and the possible effect of subsequent infections. Individuals with a diagnosis of epilepsy or any mental disorder before exposure will be excluded and, among other confounders, we will adjust for place of birth and a family history of psychiatric disorders. An additional analysis performed in a case-sibling design will give an adjustment of several socioeconomic aspects in an indirect manner. The analyses will be based on data ranging from 1 January 1977 to 31 December 2010 which gives a period of more than three decades. Data will be analyzed using survival analysis techniques and the incidence rate ratios (IRRs) are used as an approximation of the relative risk estimated by Poisson regression. Results: Results will be ready for presentation at the conference. Discussion: The present population-based cohort study will be the largest study so far and be the first to consider whether inflammation plays a part in the relationship between head injury and psychiatric disorders. We will exclude persons diagnosed with epilepsy and include the diagnoses of organic mental disorders as outcome – aspects that have rarely been taken into consideration in previous studies. Furthermore, we will include a combined group of fractures not involving the skull or spine as a comparison group in order to estimate if the results are due to increased risk behaviour in not yet diagnosed psychiatric patients.