Michael Eriksen Benros

Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials.

IMPORTANCE Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents. OBJECTIVE To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions. DATA SOURCES Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles. STUDY SELECTION Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression. DATA EXTRACTION AND SYNTHESIS Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated. MAIN OUTCOMES AND MEASURES Depression scores after treatment and adverse effects. RESULTS Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and 4 investigated cytokine inhibitors (n=2,004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2=90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, -0.54; 95% CI, -1.08 to -0.01; I2=68%) and depressive symptoms (SMD, -0.27; 95% CI, -0.53 to -0.01; I2=68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2=0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity. CONCLUSIONS AND RELEVANCE Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.

Autoimmune diseases and severe infections as risk factors for schizophrenia: A 30-year population-based register study

OBJECTIVE Autoimmune diseases have been associated with an increased risk of schizophrenia. It has been suggested that brain-reactive autoantibodies are part of the mechanisms behind this association. Furthermore, an increased permeability of the blood-brain barrier has been observed during periods of infection and inflammation. The authors therefore investigated whether autoimmune diseases combined with exposures to severe infections may increase the risk of schizophrenia METHOD Nationwide population-based registers in Denmark were linked, and the data were analyzed in a cohort study using survival analysis. All analyses were adjusted for calendar year, age, and sex. Incidence rate ratios and accompanying 95% confidence intervals (CIs) as measures of relative risk were used. RESULTS A prior autoimmune disease increased the risk of schizophrenia by 29% (incidence rate ratio=1.29; 95% CI=1.18-1.41). Any history of hospitalization with infection increased the risk of schizophrenia by 60% (incidence rate ratio=1.60; 95% CI=1.56-1.64). When the two risk factors were combined, the risk of schizophrenia was increased even further (incidence rate ratio=2.25; 95% CI=2.04-2.46). The risk of schizophrenia was increased in a dose-response relationship, where three or more infections and an autoimmune disease were associated with an incidence rate ratio of 3.40 (95% CI=2.91-3.94). The results remained significant after adjusting for substance use disorders and family history of psychiatric disorders. Hospital contact with infection occurred in nearly 24% of individuals prior to a schizophrenia diagnosis. CONCLUSIONS Autoimmune disease and the number of infections requiring hospitalization are risk factors for schizophrenia. The increased risk is compatible with an immunological hypothesis in subgroups of schizophrenia patients.

Autoimmune Diseases and Severe Infections as Risk Factors for Mood Disorders: A Nationwide Study

IMPORTANCE Mood disorders frequently co-occur with medical diseases that involve inflammatory pathophysiologic mechanisms. Immune responses can affect the brain and might increase the risk of mood disorders, but longitudinal studies of comorbidity are lacking. OBJECTIVE To estimate the effect of autoimmune diseases and infections on the risk of developing mood disorders. DESIGN Nationwide, population-based, prospective cohort study with 78 million person-years of follow-up. Data were analyzed with survival analysis techniques and adjusted for calendar year, age, and sex. SETTING Individual data drawn from Danish longitudinal registers. PARTICIPANTS A total of 3.56 million people born between 1945 and 1996 were followed up from January 1, 1977, through December 31, 2010, with 91, 637 people having hospital contacts for mood disorders. MAIN OUTCOMES AND MEASURES The risk of a first lifetime diagnosis of mood disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% CIs are used as measures of relative risk. RESULTS A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45% (IRR, 1.45; 95% CI, 1.39-1.52). Any history of hospitalization for infection increased the risk of later mood disorders by 62% (IRR, 1.62; 95% CI, 1.60-1.64). The 2 risk factors interacted in synergy and increased the risk of subsequent mood disorders even further (IRR, 2.35; 95% CI, 2.25-2.46). The number of infections and autoimmune diseases increased the risk of mood disorders in a dose-response relationship. Approximately one-third (32%) of the participants diagnosed as having a mood disorder had a previous hospital contact because of an infection, whereas 5% had a previous hospital contact because of an autoimmune disease. CONCLUSIONS AND RELEVANCE Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis. These associations seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients.

Autoimmune diseases and infections as risk factors for schizophrenia.

Immunological hypotheses have become increasingly prominent when studying the etiology of schizophrenia. Autoimmune diseases, and especially the number of infections requiring hospitalization, have been identified as significant risk factors for schizophrenia in a dose–response relationship, which seem compatible with an immunological hypothesis for subgroups of patients with schizophrenia. Inflammation and infections may affect the brain through many different pathways that are not necessarily mutually exclusive and can possibly increase the risk of schizophrenia in vulnerable individuals. However, the findings could also be an epiphenomenon and not causal, due to, for instance, common genetic vulnerability, which could be supported by the observations of an increased prevalence of autoimmune diseases and infections in parents of patients with schizophrenia. Nevertheless, autoimmune diseases and infections should be considered in the treatment of individuals with schizophrenia symptoms, and further research is needed of the immune systems possible contributing pathogenic factors in the etiology of schizophrenia.

The Epidemiologic Evidence Linking Autoimmune Diseases and Psychosis

This review summarizes the epidemiologic evidence linking autoimmune diseases and psychosis. The associations between autoimmune diseases and psychosis have been studied for more than a half century, but research has intensified within the last decades, since psychosis has been associated with genetic markers of the immune system and with excess autoreactivity and other immune alterations. A range of psychiatric disorders, including psychosis, have been observed to occur more frequently in some autoimmune diseases, such as systemic lupus erythematosus and multiple sclerosis. Many autoimmune diseases involve multiple organs and general dysfunction of the immune system, which could affect the brain and induce psychiatric symptoms. Most studies have been cross-sectional, observing an increased prevalence of a broad number of autoimmune diseases in people with psychotic disorders. Furthermore, there is some evidence of associations of psychosis with a family history of autoimmune disorders and vice versa. Additionally, several autoimmune diseases, individually and in aggregate, have been identified as raising the risk for psychotic disorders in longitudinal studies. The associations have been suspected to be caused by inflammation or brain-reactive antibodies associated with the autoimmune diseases. However, the associations could also be caused by shared genetic factors or common etiologic components such as infections. Infections can induce the development of autoimmune diseases and autoantibodies, possibly affecting the brain. Autoimmune diseases and brain-reactive antibodies should be considered by clinicians in the treatment of individuals with psychotic symptoms, and even if the association is not causal, treatment would probably still improve quality of life and survival.

Head injury as risk factor for psychiatric disorders: A nationwide register-based follow-up study of 113,906 persons with head injury

OBJECTIVE Studies investigating the relationship between head injury and subsequent psychiatric disorders often suffer from methodological weaknesses and show conflicting results. The authors investigated the incidence of severe psychiatric disorders following hospital contact for head injury. METHOD The authors used linkable Danish nationwide population-based registers to investigate the incidence of schizophrenia spectrum disorders, unipolar depression, bipolar disorder, and organic mental disorders in 113,906 persons who had suffered head injuries. Data were analyzed by survival analysis and adjusted for gender, age, calendar year, presence of a psychiatric family history, epilepsy, infections, autoimmune diseases, and fractures not involving the skull or spine. RESULTS Head injury was associated with a higher risk of schizophrenia (incidence rate ratio [IRR]=1.65, 95% CI=1.55-1.75), depression (IRR=1.59 95% CI=1.53-1.65), bipolar disorder (IRR=1.28, 95% CI=1.10-1.48), and organic mental disorders (IRR=4.39, 95% CI=3.86-4.99). This effect was larger than that of fractures not involving the skull or spine for schizophrenia, depression, and organic mental disorders, which suggests that the results were not merely due to accident proneness. Head injury between ages 11 and 15 years was the strongest predictor for subsequent development of schizophrenia, depression, and bipolar disorder. The added risk of mental illness following head injury did not differ between individuals with and without a psychiatric family history. CONCLUSIONS This is the largest study to date investigating head injury and subsequent mental illness. The authors demonstrated an increase in risk for all psychiatric outcomes after head injury. The effect did not seem to be solely due to accident proneness, and the added risk was not more pronounced in persons with a psychiatric family history.

Association between alcohol and substance use disorders and all-cause and cause-specific mortality in schizophrenia, bipolar disorder, and unipolar depression: a nationwide, prospective, register-based study

BACKGROUND People with severe mental illness have both increased mortality and are more likely to have a substance use disorder. We assessed the association between mortality and lifetime substance use disorder in patients with schizophrenia, bipolar disorder, or unipolar depression. METHODS In this prospective, register-based cohort study, we obtained data for all people with schizophrenia, bipolar disorder, or unipolar depression born in Denmark in 1955 or later from linked nationwide registers. We obtained information about treatment for substance use disorders (categorised into treatment for alcohol, cannabis, or hard drug misuse), date of death, primary cause of death, and education level. We calculated hazard ratios (HRs) for all-cause mortality and subhazard ratios (SHRs) for cause-specific mortality associated with substance use disorder of alcohol, cannabis, or hard drugs. We calculated standardised mortality ratios (SMRs) to compare the mortality in the study populations to that of the background population. FINDINGS Our population included 41 470 people with schizophrenia, 11 739 people with bipolar disorder, and 88 270 people with depression. In schizophrenia, the SMR in those with lifetime substance use disorder was 8·46 (95% CI 8·14-8·79), compared with 3·63 (3·42-3·83) in those without. The respective SMRs in bipolar disorder were 6·47 (5·87-7·06) and 2·93 (2·56-3·29), and in depression were 6·08 (5·82-6·34) and 1·93 (1·82-2·05). In schizophrenia, all substance use disorders were significantly associated with increased risk of all-cause mortality, both individually (alcohol, HR 1·52 [95% CI 1·40-1·65], p<0·0001; cannabis, 1·24 [1·04-1·48], p=0·0174; hard drugs, 1·78 [1·56-2·04], p<0·0001) and when combined. In bipolar disorder or depression, only substance use disorders of alcohol (bipolar disorder, HR 1·52 [95% CI 1·27-1·81], p<0·0001; depression, 2·01 [1·86-2·18], p<0·0001) or hard drugs (bipolar disorder, 1·89 [1·34-2·66], p=0·0003; depression, 2·27 [1·98-2·60], p<0·0001) increased risk of all-cause mortality individually. INTERPRETATION Mortality in people with mental illness is far higher in individuals with substance use disorders than in those without, particularly in people who misuse alcohol and hard drugs. Mortality-reducing interventions should focus on patients with a dual diagnosis and seek to prevent or treat substance use disorders. FUNDING The Lundbeck Foundation.

The association between depressive symptoms, cognitive function, and inflammation in major depression.

The purpose of this study was to assess the association between IL-6 and CRP with depressive items and cognitive function. We included 112 outpatients with major depression from an exercise trial and 57 healthy controls. IL-6, high sensitive CRP (hsCRP), and cognitive function were assessed in all subjects. After baseline assessment, patients were randomised to either a 3months exercise intervention or an exercise control group. Post-intervention IL-6, hsCRP, depressive symptoms, and cognitive function were reassessed in the patient group. IL-6 and hsCRP were significantly increased in depressed patients compared to healthy controls (p=0.02 and 0.04). These differences were no longer significant after adjustment for lifestyle associated variables. We found no association between immune markers and specific depressive symptoms at baseline or as change over time. Regarding the cognitive tests, IL-6 was positively associated with Serial sevens (p=0.008) and hsCRP was inversely associated with Trail making A (p=0.02) and design fluency (p=0.001) at baseline. At 3months follow-up IL-6 and hsCRP levels did not significantly change from baseline and did not differ between the two patient groups. Depression scores was lower compared to baseline but did not differ between groups. Combining the two groups, a decrease in IL-6 was associated to decreased verbal fluency (p=0.02), and a decrease in hsCRP was associated with improvement in Trail making A (p=0.005). In conclusion, the level of IL-6 and hsCRP was increased in depressed outpatients but was not associated to specific depressive symptoms. In terms of cognitive function, we found that higher hsCRP levels were associated to lower psychomotor speed both at baseline and at follow-up.

Schizophrenia in patients with atopic disorders with particular emphasis on asthma: A Danish population-based study

OBJECTIVE Autoimmune diseases and infections have been associated with an increased risk of schizophrenia that could be rooted in inflammatory mechanisms. However, other diseases characterized by a heightened immune response, such as atopic disorders, remain to be thoroughly investigated. The aim of this study was to investigate whether atopic disorders in the individual or in a first-degree relative affect the risk of developing schizophrenia. METHOD We linked two nationwide population-based registers: the Danish Psychiatric Central Register and the National Hospital Register. Two longitudinal designs were used: a cohort study and a case/sibling study. Rate ratios (RRs) and accompanying 95% confidence intervals (CIs) were obtained. RESULTS Hospital contact with any atopic disorder increased the RR of schizophrenia by 1.45 (95% CI=1.31-1.90). The increased risk was mainly driven by asthma: 1.59 (95% CI=1.31-1.90); this was confirmed when cases were compared with siblings instead of the background population. Hospital contact with other included atopic disorders (atopic dermatitis, urticaria and allergic rhinitis) increased the risk of schizophrenia significantly only if they were combined into one group. Hospital contact with asthma in a first-degree relative did not significantly increase the risk of schizophrenia. CONCLUSION This study indicates the existence of an association between atopic disorders in general and asthma in particular and the risk of developing schizophrenia. The study adds to a growing body of literature suggesting the possible involvement of immune processes in the pathophysiology of schizophrenia.

Hospital Contacts With Infection and Risk of Schizophrenia: A Population-Based Cohort Study With Linkage of Danish National Registers

Infections and immune responses have been suggested to play an important role in the etiology of schizophrenia. Several studies have reported associations between maternal infections during pregnancy and the childs risk of schizophrenia; however, infection during childhood and adolescence unrelated to maternal infection during pregnancy has not been studied to nearly the same extent and the results are far from conclusive. Data were drawn from 2 population-based registers, the Danish Psychiatric Central Register and the Danish National Hospital Register. We used a historical population-based cohort design and selected all individuals born in Denmark between 1981 and 1996 (n = 843 390). We identified all individuals with a first-time hospital contact with schizophrenia from 1991 through 2010. Out of the 3409 individuals diagnosed with schizophrenia, a total of 1549 individuals had had a hospital contact with infection before their schizophrenia diagnosis (45%). Our results indicate that individuals who have had a hospital contact with infection are more likely to develop schizophrenia (relative risk [RR] = 1.41; 95% CI: 1.32-1.51) than individuals who had not had such a hospital contact. Bacterial infection was the type of infection that was associated with the highest risk of schizophrenia (RR = 1.63; 95% CI: 1.47-1.82). Our study does not exclude that a certain type of infection may have a specific effect; yet, it does suggest that schizophrenia is associated with a wide range of infections. This association may be due to inflammatory responses affecting the brain or genetic and environmental risk factors aggregating in families.