Nils Eiel Steen

Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor

BACKGROUND Alterations in the inflammatory system have been associated with schizophrenia and major depression, while bipolar disorder has been less studied. Most previous studies examined small samples, and the literature is inconsistent with regard to specific underlying immune mechanisms. In the present study, we examined markers representing different inflammatory pathways, and the aim was to investigate whether the levels of inflammatory parameters in a representative sample of bipolar disorder and schizophrenia are elevated compared to healthy controls, and to investigate whether the inflammatory profile is different between the groups. METHODS Plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), high-sensitivity CRP (hs-CRP), soluble CD40L ligand (sCD40L), and von Willebrand factor (vWf) were measured with ELISA techniques in a catchment area based sample of consecutively referred patients with severe mental disorders [N = 311, comprising bipolar disorder (n = 125) and schizophrenia (n = 186)] and in healthy volunteers (n = 244). RESULTS Plasma levels of sTNF-R1 and vWf were statistically significantly increased in both bipolar disorder and schizophrenia compared to controls (p < 0.00001), and were also increased in unmedicated patients, but there were no major differences between the two diagnostic groups. Controlling for age, gender, ethnicity, cardiovascular disorders, kidney and liver function, and other confounders did not affect the results. There were no differences in other inflammation factors between the groups. CONCLUSION The present results indicate specific alterations of endothelium-related inflammation processes in both bipolar disorder and schizophrenia.

Suicidality before and in the early phases of first episode psychosis

INTRODUCTION The suicide risk in psychotic disorders is highest in the early phases of illness. Studies have typically focused on suicidality from treatment start rather than actual onset of psychosis. This study explored the prevalence and characteristics of suicidality in patients with a first episode of psychosis (FEP) in two time intervals: 1) prior to study entry and 2) explicitly in the period of untreated psychosis. METHOD One hundred seventy FEP-patients were interviewed as soon as possible after treatment start. The interview included assessments of diagnoses, suicidality, symptoms, substance use, and premorbid functioning. RESULTS Nearly 26% of the patients attempted suicide prior to study entry and 14% made suicide attempts during the period of untreated psychosis. Of the patients who had been suicidal (i.e. experienced suicidal ideation or attempts), 70% were suicidal during the period of untreated psychosis. Suicide attempts prior to study entry were associated with female gender, more depressive episodes, younger age at psychosis onset, and history of alcohol disorder. Suicide attempts during untreated psychosis were also associated with more depressive episodes and younger age at illness onset, in addition to drug use the last six months and longer duration of untreated psychosis (DUP). CONCLUSION The prevalence of suicidality before and in the early phases of FEP is high, especially during untreated psychosis. As prolonged DUP is associated with suicide attempts during the period of untreated psychosis, reducing the DUP could have the effect of reducing the prevalence of suicide attempts in patients with FEP.

Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder

BACKGROUND Previous studies suggest elevated inflammation in schizophrenia and bipolar disorder, with increased activity of the Interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF)-alpha, von Willebrand factor (vWf) and osteoprotegerin (OPG). It is unclear how immune activation is involved in the psychopathology. We investigated if elevated inflammation was associated with disease severity (trait) or current symptom level (state), comparing psychotic with general characteristics. METHODS Plasma levels of sTNF receptor 1 (sTNF-R1), IL-1 receptor antagonist (IL-1Ra), IL-6, vWf and OPG were measured with ELISA techniques in 322 patients with schizophrenia spectrum and bipolar disorder. Current symptom level (state) was measured with Global Assessment of Functioning (GAF) and Positive and Negative Syndrome Scale (PANSS). Disease severity (trait) was measured with premorbid adjustment scale (PAS), age at onset, number of psychotic episodes and number and length of hospitalizations. RESULTS After controlling for confounders, IL-1Ra and TNF-R1 were independently associated with GAF, and significantly correlated with PANSS negative and positive, respectively. In addition, Il-1Ra was associated with PAS, and sTNF-R1 with number of hospitalizations and psychotic episodes. VWf was significantly correlated with psychotic episodes, OPG with hospitalizations and IL-6 with history of psychosis. Linear regression analysis showed that GAF remained associated with sTNF-R1 and IL-1Ra with PANSS, after controlling for the other clinical measures. CONCLUSIONS This supports that inflammatory markers, particularly IL-1Ra and sTNF-R1 are associated with both general disease severity and psychotic features. This supports a role of immune activation in the core pathological mechanisms of severe mental disorders.

BDNF val66met modulates the association between childhood trauma, cognitive and brain abnormalities in psychoses

OBJECTIVE Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF val66met variant modulates the association between high levels of childhood abuse, cognitive function, and brain abnormalities in psychoses. METHOD 249 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited to the TOP research study (mean±age: 30.7±10.9; gender: 49% males). History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Cognitive function was assessed through a standardized neuropsychological test battery. BDNF val66met was genotyped using standardized procedures. A sub-sample of n=106 Caucasians with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder (mean±age: 32.67±10.85; 49% males) had data on sMRI. RESULTS Carriers of the Methionine (met) allele exposed to high level of childhood abuse demonstrated significantly poorer cognitive functioning compared to homozygotic Valine (val/val) carriers. Taking in consideration multiple testing, using a more conservative p value, this was still shown for physical abuse and emotional abuse, as well as a trend level for sexual abuse. Further, met carriers exposed to high level of childhood sexual abuse showed reduced right hippocampal volume (r(2)=0.43; p=0.008), and larger right and left lateral ventricles (r(2)=0.37; p=0.002, and r(2)=0.27; p=0.009, respectively). Our findings were independent of age, gender, diagnosis and intracranial volume. CONCLUSION Our data demonstrate that in patients with psychoses, met carriers of the BDNF val66met with high level of childhood abuse have more cognitive and brain abnormalities than all other groups.

Suicidality in first episode psychosis is associated with insight and negative beliefs about psychosis

INTRODUCTION Suicidal behaviour is prevalent in psychotic disorders. Insight has been found to be associated with increased risk for suicidal behaviour, but not consistently. A possible explanation for this is that insight has different consequences for patients depending on their beliefs about psychosis. The present study investigated whether a relationship between insight, negative beliefs about psychosis and suicidality was mediated by depressive symptoms, and if negative beliefs about psychosis moderated the relationship between insight and suicidality in patients with a first episode of psychosis (FEP). METHOD One hundred ninety-four FEP-patients were assessed with a clinical interview for diagnosis, symptoms, functioning, substance use, suicidality, insight, and beliefs about psychosis. RESULTS Nearly 46% of the patients were currently suicidal. Depressive symptoms, having a schizophrenia spectrum disorder, insight, and beliefs about negative outcomes for psychosis were independently associated with current suicidality; contradicting a mediating effect of depressive symptoms. Negative beliefs about psychosis did not moderate the effect of insight on current suicidality. CONCLUSION The results indicate that more depressive symptoms, higher insight, and negative beliefs about psychosis increase the risk for suicidality in FEP-patients. The findings imply that monitoring insight should be part of assessing the suicide risk in patients with FEP, and that treating depression and counteracting negative beliefs about psychosis may possibly reduce the risk for suicidality.

Serotonin Transporter Gene Polymorphism, Childhood Trauma, and Cognition in Patients With Psychotic Disorders

OBJECTIVE The functional polymorphism in the promoter region of the SLC6A4/5-HTT serotonin transporter gene (5-HTTLPR) has been linked to altered stress response. Carriers of the short (s-) allele have increased negative psychological reactions and stress hormone release compared with carriers of the long (l-) allele, interacting with severe life events including childhood trauma. High stress levels are associated with cognitive impairments in a variety of clinical and experimental studies. Patients with psychotic disorders are characterized both by more childhood traumatic events and abnormal stress responses and by significant but highly variable cognitive dysfunction. We hypothesize that 5-HTTLPR variations and long-term effects of childhood trauma interact and contribute to some of the variation in cognitive dysfunction seen in patients with psychotic disorders. METHODS Patients with psychotic disorders (schizophrenia and affective spectrums) were recruited from a catchment area-based treatment organization. History of childhood abuse was obtained by the Childhood Trauma Questionnaire. Cognitive function was assessed through a comprehensive, standardized neuropsychological test battery. 5-HTTLPR genotypes were analyzed using standard polymerase chain reaction. RESULTS We observed a significant interaction between 5-HTTLPR variants and childhood trauma across cognitive domains; here, homozygotic s-carriers exposed to high levels of childhood trauma (physical neglect and abuse) had significantly poorer cognitive functioning than all other groups. CONCLUSIONS Our results need replication but underline the importance of investigating childhood trauma and its interaction with genetic markers when studying cognitive dysfunction in patients with psychotic disorders.

High prevalence of childhood trauma in patients with schizophrenia spectrum and affective disorder

OBJECTIVE Childhood trauma (CT) is a major risk factor for various psychiatric disorders. We wanted to determine the prevalence of CT in a catchment area-based sample of schizophrenia spectrum and affective disorder (including bipolar disorder and depressive episodes with psychotic features) and to explore potential differences in types of CT between the diagnostic groups. METHOD Three hundred five patients were recruited consecutively from psychiatric units at 3 major hospitals in Oslo, Norway, diagnosed with Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Traumatic childhood events were assessed with Childhood Trauma Questionnaire. RESULTS Eighty-two percent of the patients had experienced one or more CT events, the most frequent subtype of trauma being emotional neglect. The schizophrenia spectrum group reported significantly more physical abuse and physical neglect than the affective group. CONCLUSION A high prevalence of CT in patients with severe mental disorder was detected. This reminds us of the importance of exploring this issue when we treat such patients. The mechanisms behind these differences are unclear. Further research is needed to study potential associations between CT and the clinical picture of the disorder.

Is cognitive impairment following early life stress in severe mental disorders based on specific or general cognitive functioning

Schizophrenia spectrum and bipolar disorder are characterized by high levels of childhood trauma as well as of cognitive dysfunction. Our aim is to investigate the association between these two factors in the largest study in the literature so far. A total of 406 patients with schizophrenia spectrum- or bipolar disorders were recruited from a catchment area based organization in Oslo, Norway. Information about early life stress was obtained using the Childhood Trauma Questionnaire (CTQ). Cognitive function was assessed through a comprehensive and standardized neuropsychological test battery. Physical abuse, sexual abuse and physical neglect were significantly associated with reduced scores on working memory and executive function scales (p=0.04 to p<0.001), and verbal and performance tasks from the Wechsler Abbreviated Scale of Intelligence (WASI) (p=0.059 to p<0.001). When verbal and performance tasks from the WASI were added into a multivariate regression model, the association between CTQ and the specific cognitive domains decreased, and only WASI scores remained statistically significant. Our results indicate that childhood trauma is associated with a reduction in cognitive function across cognitive domains in patients with schizophrenia spectrum- and bipolar disorders, in particular working memory and executive function as well as general cognition. Moreover, these dysfunctions seem to be driven by underlying deficits in general cognitive tasks as measured by the WASI.

Increased Systemic Cortisol Metabolism in Patients With Schizophrenia and Bipolar Disorder: A Mechanism for Increased Stress Vulnerability?

OBJECTIVE The hypothalamic-pituitary-adrenal (HPA) axis seems dysregulated and part of the pathophysiology in bipolar disorder and schizophrenia, but the underlying mechanisms are unknown. Recent evidence indicates that systemic cortisol metabolism influences blood cortisol levels and HPA axis functioning. Our objective was to estimate systemic cortisol metabolism by means of the activity of 5α-reductase, 5β-reductase, and 11β-hydroxysteroid dehydrogenase (11β-HSD) in patients with bipolar disorder and schizophrenia spectrum disorders compared to healthy controls. METHOD Inpatients and outpatients aged 18 to 65 years with DSM-IV bipolar disorder (n = 69) or schizophrenia (n = 87) were consecutively recruited to the catchment area-based Thematically Organized Psychosis Research (TOP) study. Healthy controls (n = 169) were randomly selected from statistical records from the same catchment area and were contacted by letter inviting them to participate. Spot urine samples were collected in a cross-sectional manner from November 2006 to November 2008. Urinary free cortisol and cortisone and their metabolites were analyzed with liquid chromatography tandem mass spectrometry and used as indicators of 5α-reductase, 5β-reductase, and 11β-HSD activity. RESULTS The combined patient group had increased activity of 5α-reductase, 5β-reductase, and 11β-HSD2 (all P < .001) compared to controls. Elevated systemic cortisol metabolism was present in both schizophrenia (5α-reductase, 5β-reductase, and 11β-HSD2; all P < .001) and bipolar disorder (5α-reductase [P = .016], 5β-reductase [P = .001], and 11β-HSD2 [P = .007]). CONCLUSIONS The results indicate increased activity of cortisol metabolism in patients with bipolar disorder and schizophrenia compared to healthy controls and suggest that increased systemic cortisol metabolism is involved in the pathophysiology and stress vulnerability in these severe mental disorders. The findings should be explored further in terms of potential new drug targets, and they add to the physiologic rationale for stress coping strategies in these patient groups.

Patterns of childhood adverse events are associated with clinical characteristics of bipolar disorder

BackgroundPrevious studies in bipolar disorder investigating childhood trauma and clinical presentations of the illness have mainly focused on physical and sexual abuse. Our aim was to explore further the relationship between childhood trauma and disease characteristics in bipolar disorder to determine which clinical characteristics were most strongly associated with childhood trauma total score, as well as subtypes of adverse childhood events, including physical, sexual, emotional abuse and neglect.Methods141 Patients with bipolar disorder were consecutively recruited, and disease history and clinical characteristics were assessed. History of childhood abuse was obtained using the Childhood Trauma Questionnaire (CTQ). Statistical methods used were factor analysis, Poisson and linear regression, and generalized additive modeling (GAM).ResultsThe factor analysis of CTQ identified three factors: emotional abuse/neglect, sexual abuse and physical abuse. There were significant associations between CTQ total score and earlier onset of illness, reduced level of psychosocial functioning (GAF; Global Assessment of Functioning) and decreased number of hospitalization, which mainly were due to the factor emotional abuse/neglect. Physical abuse was significantly associated with lower GAF scores, and increased number of mood episodes, as well as self-harm. Sexual abuse was significantly associated with increased number of mood episodes. For mood episodes and self-harm the associations were characterized by great variance and fluctuations.ConclusionsOur results suggest that childhood trauma is associated with a more severe course of bipolar illness. Further, childhood abuse (physical and sexual), as well as emotional abuse and neglect were significantly associated with accelerating staging process of bipolar disorder. By using specific trauma factors (physical abuse, sexual abuse and emotional abuse/neglect) the associations become both more precise, and diverse.