Steinar Lorentzen

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.

A genome-wide association study of bipolar disorder in Norwegian individuals, followed by replication in Icelandic sample

BACKGROUND In the present study we investigated genetic variants associated with bipolar disorder in a homogenous Norwegian sample, and potential genetic overlap with schizophrenia, using the Affymetrix 6.0 array. METHODS We carried out a genome-wide association study (GWAS) by genotyping 620 390 single-nucleotide polymorphisms (SNPs) in a case-control sample of Norwegian origin (the TOP study) including bipolar disorder (n=194), healthy controls (n=336) and schizophrenia (n=230), followed by replication and combined analysis in a genetically concordant Icelandic sample of bipolar disorder (n=435), and healthy controls (n=10,258). RESULTS We selected 1000 markers with the lowest P values in the TOP discovery GWAS and tested these (or their surrogates) for association in the Icelandic replication sample. Polymorphisms on 35 loci were confirmed associated with bipolar disorder (nominal P value<0.05; not corrected for multiple testing) in the replication sample. The most significant markers were located in DLEU2, GUCY1B2, PKIA, CCL2, CNTNAP5, DPP10, and FBN1. The combined group of schizophrenia and bipolar disorder compared to controls did not provide additional significant findings. LIMITATIONS Relatively small number of samples. CONCLUSIONS We detected weak but reproducible association with markers in several genes, in proximity to susceptibility loci found in previous GWAS studies of bipolar disorder. Further work is required to study their localization, expression, and regulation and international meta-analytic efforts will help to further elucidate their role.

Childhood trauma is associated with severe clinical characteristics of bipolar disorders.

OBJECTIVE Beyond genetic risk variants, the pathophysiology of bipolar disorders is likely to be partly determined by environmental susceptibility factors. Our study is one of the first to investigate, in a large sample of well-characterized bipolar patients, associations between clinical presentations and childhood trauma subtypes, including neglect and abuse items. METHOD 587 patients with DSM-IV-defined bipolar disorder were recruited from France and Norway between 1996-2008 and 2007-2012, respectively. History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Clinical variables were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders (Norwegian sample) or the Diagnostic Interview for Genetic Studies (French sample). RESULTS Earlier age at onset of bipolar illness, suicide attempts, rapid cycling, and an increased number of depressive episodes each had significant associations (P ≤ .001) with at least 1 subtype of childhood trauma (emotional abuse, sexual abuse, and emotional neglect). Multivariate analyses investigating trauma variables together showed that both emotional and sexual abuse were independent predictors of lower age at onset (P = .002 for each) and history of suicide attempts (OR = 1.60 [95% CI, 1.07 to 2.39], P = .023; OR = 1.80 [95% CI, 1.14 to 2.86], P = .012, respectively), while sexual abuse was the strongest predictor of rapid cycling (OR = 2.04 [95% CI, 1.21 to 3.42], P = .007). Females reported overall higher childhood trauma frequency and greater associations to clinical expressions than males (P values < .05). CONCLUSIONS Our results demonstrate consistent associations between childhood trauma and more severe clinical characteristics in bipolar disorder. Further, they show the importance of including emotional abuse as well as the more frequently investigated sexual abuse when targeting clinical characteristics of bipolar disorder.

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.

Therapeutic alliance, cohesion and outcome in a long-term analytic group. A preliminary study.

We studied the ongoing relationship of patients and their therapist in a long-term, analytic group. The therapeutic alliance was rated weekly and group cohesion was rated every month, by patients and therapist. The patients’ symptoms (SCL-90-R) and interpersonal problems (IIP-C) were rated every third month during therapy (self-reports). There was a steady increase in the alliance ratings by patients and therapist during the first 2 years of therapy. This differs from findings in short-term therapies, where the alliance quickly reaches a high level and then remains stable throughout therapy. Therapist ratings of early alliance correlated significantly with positive symptomatic outcome, but did not predict interpersonal change. Patients’ alliance ratings did not predict change. Early cohesion ratings did not predict change. The concordance between the patients’ and the therapists alliance ratings was highest between 16 and 30 sessions, and was essentially maintained throughout therapy. An early concordance of patient and therapist alliance ratings predicted a better symptomatic outcome. The measures of therapeutic alliance and cohesion used in this study seem to address different elements in the group process.

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.

Change During and After Long-term Analytic Group Psychotherapy

Abstract There are very few empirical studies of long-term, analytic group psychotherapy. Sixty-nine patients in long-term analytic group psychotherapy were evaluated from pretherapy to posttherapy, and one year after termination. The primary outcome measures were the Symptom Checklist-90 (Revised) and the Inventory of Interpersonal Problems. In addition, the Global Assessment of Functioning (GAF) was scored independently by two evaluators. The average time in treatment was 32.5 months. The patients improved significantly during treatment, up to 30 months, on all measures. The improvement continued during the follow-up period. Sixty to 86% of the patients were recovered or significantly changed at follow-up.

Modeling group process constructs at three stages in group psychotherapy

Abstract This study examined the relationships among group therapy processes measured by the Working Alliance Inventory–Short Form, the Therapeutic Factors Inventory Cohesiveness subscale, and the Group Climate Questionnaire–Short Form in a sample of 145 patients attending 18 psychodynamic groups. Five hypothesized models were tested early in therapy (Sessions 3 and 4) using multilevel confirmatory factor analysis. Two three-factor models approached conventional standards of model fit. By merging these two models, a three-factor model consisting of member–leader alliance, positive bonding relationship, and negative relationship fit the data well. Later in therapy, member–leader bonding was no longer important to member–group cohesion, indicating that cohesion and alliance and the member–leader versus member–group bonding represent different processes.