Mari Nerhus

Altered systemic cortisol metabolism in bipolar disorder and schizophrenia spectrum disorders

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is suggested as a pathophysiological factor in bipolar disorder and schizophrenia. Increased clearance of cortisol was recently indicated as a component in the HPA axis hyperdrive. The aim of the present study was to test the model of increased cortisol metabolism in a new replication sample separately and combined with a previously published sample of bipolar disorder and schizophrenia. Spot urine was sampled from 212 healthy controls (HC) and 221 patients with a schizophrenia spectrum disorder (SCZ, n = 115) and bipolar disorder (BD, n = 106). Of these, a subsample of 169 HC and 155 patients was included in a previous report. Urinary free cortisol, cortisone and their metabolites were measured, and the activities of 5α-reductase, 5β-reductase and 11β-HSD were estimated and analyzed for differences between groups. In the new sample, there was increased enzyme activity in SCZ for 5β-reductase (p = 0.024 vs HC; p = 0.027 vs BD) and 11β-HSD2 (p = 0.014 vs HC; p = 0.004 vs BD). In the combined sample, there was increased activity in SCZ for 5α-reductase (p < 0.001 vs HC; p = 0.020 vs BD), 5β-reductase (p < 0.001 vs HC; p = 0.045 vs BD) and 11β-HSD2 (p < 0.001 vs HC; p = 0.043 vs BD), and in BD for 5β-reductase (p = 0.002), 11β-HSD2 (p = 0.039) and 5α-reductase (trend, p = 0.084) (all vs HC). The findings confirm increased systemic cortisol metabolism in BD and SCZ. This is most consistent in SCZ, with BD taking an intermediate position. The design makes it impossible to determine the direction of the effect. However, the findings merit further study of cortisol metabolism as a possible component in the HPA axis dysfunction and pathophysiology of BD and SCZ.

Inflammatory evidence for the psychosis continuum model

BACKGROUND Inflammation and immune activation have been implicated in the pathophysiology of severe mental disorders. Previous studies of inflammatory markers, however, have been limited with somewhat inconsistent results. AIMS We aimed to determine the effect sizes of inflammatory marker alterations across diagnostic groups of the psychosis continuum and investigate association to antipsychotic medications. METHODS Plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), and von Willebrand factor (vWf) were measured in patients (n=992) with schizophrenia spectrum (SCZ, n=584), schizoaffective disorder (SA, n=93), affective spectrum disorders (AFF, n=315), and healthy controls (HC, n=638). RESULTS Levels of sTNF-R1 (p=1.8×10(-8), d=0.23) and IL-1Ra (p=0.002, d=0.16) were increased in patients compared to HC. The SCZ group had higher levels of sTNF-R1 (p=8.5×10(-8), d=0.27) and IL-1Ra (p=5.9×10(-5), d=0.25) compared to HC, and for sTNF-R1 this was also seen in the SA group (p=0.01, d=0.3) and in the AFF group (p=0.002, d=0.12). Further, IL-1Ra (p=0.004, d=0.25) and vWf (p=0.02, d=0.21) were increased in the SCZ compared to the AFF group. There was no significant association between inflammatory markers and use of antipsychotic medication. CONCLUSION We demonstrate a small increase in sTNF-R1 and IL-1Ra in patients with severe mental disorders supporting a role of inflammatory mechanisms in disease pathophysiology. The increase was more pronounced in SCZ compared to AFF supporting a continuum psychosis model related to immune factors.

Low vitamin D is associated with negative and depressive symptoms in psychotic disorders

BACKGROUND There are indications that low S-25(OH)D is associated with increased disease severity in psychotic disorder. Our first aim was to investigate the relations between low S-25(OH)D and positive, negative and depressive symptoms. Our second aim was to explore if associations between S-25(OH)D and symptoms were influenced by levels of inflammatory markers. METHODS Participants (N=358) with a medical history of one or more psychotic episodes were recruited. Current symptomatology was assessed by The Structured Interview for the Positive and Negative Syndrome Scaleanalyzed by a five-factor model. The Calgary Depression Scale for Schizophrenia was used to assess depression and suicidal ideation. Blood samples were analyzed for S-25(OH)D, CRP, sTNF-R1, IL-Ra and OPG. We performed bivariate correlations and multiple regression models to evaluate the effect of S-25(OH)D on the outcomes. RESULTS Low S-25(OH)D was significantly associated with negative symptoms (adjusted R2=0.113, F(6,357)=8.58, p<0.001) and with depression (adjusted R2=0.045, F(4,357)=5.233, p<0.001) when adjusting for possible confounding factors (i.e. gender, education, diagnose, hospitalization status, ethnicity, season and thyroid status). CRP was correlated with both S-25(OH)D (rho=-0.13, p=0.02) and negative symptoms (rho=0.14, p=0.01), but did not act as a mediator. The correlations between S-25(OH)D and the inflammatory markers sTNF-R1, IL-Ra and OPG were not significant. CONCLUSION There is a strong association between low S-25(OH)D and higher negative and depressive symptoms in psychotic disorders. Randomized controlled trials should be performed to investigate the effect of vitamin D supplementation as adjuvant treatment strategy in patients with prominent negative or depressive symptoms.

Vitamin D status in psychotic disorder patients and healthy controls – The influence of ethnic background

Vitamin D deficiency is common among patients with psychotic disorders and could be due to unknown disease mechanisms or contingent factors. However most studies are performed in chronic patients and have often failed to address the influence of ethnicity on vitamin D levels in clinical samples. We investigated serum concentrations of 25-hydroxy vitamin D (S-25 OH D) in first episode patients compared to patients with multi episodes and healthy controls; with a specific focus on differences between visible ethnic minorities and participants from the majority population. A total of 284 participants were included in this cross-sectional study. First episode patients with a DSM-IV psychotic disorder were matched on age, gender and ethnicity to participants from a multi episode patient sample (1:1) and healthy controls (1:2). We did not find any differences between either patient groups or the healthy controls, but participants from visible ethnic minorities had significantly lower S-25 OH D than participants from the majority population. This implies that S-25 OH D should be routinely measured in persons from visible ethnic minorities since low levels are associated with higher levels of depressive symptoms.

Resting-state high-frequency heart rate variability is related to respiratory frequency in individuals with severe mental illness but not healthy controls

Heart rate variability (HRV) has become central to biobehavioral models of self-regulation and interpersonal interaction. While research on healthy populations suggests changes in respiratory frequency do not affect short-term HRV, thus negating the need to include respiratory frequency as a HRV covariate, the nature of the relationship between these two variables in psychiatric illness is poorly understood. Therefore, the aim of this study was to investigate the association between HRV and respiratory frequency in a sample of individuals with severe psychiatric illness (n = 55) and a healthy control comparison group (n = 149). While there was no significant correlation between HF-HRV and respiration in the control group, we observed a significant negative correlation in the psychiatric illness group, with a 94.1% probability that these two relationships are different. Thus, we provide preliminary evidence suggesting that HF-HRV is related to respiratory frequency in severe mental illness, but not in healthy controls, suggesting that HRV research in this population may need to account for respiratory frequency. Future work is required to better understand the complex relationship between respiration and HRV in other clinical samples with psychiatric diseases.

Migrant background and ethnic minority status as predictors for duration of untreated psychosis

The aim of the study was to explore if patients with migration and/or ethnic minority background have longer duration of untreated psychosis (DUP) than patients from the reference population, and in case to what extent this was best explained by ethnic minority status or migration background, including age at migration.

Childhood trauma mediates the association between ethnic minority status and more severe hallucinations in psychotic disorder

BACKGROUND Ethnic minority status and childhood trauma are established risk factors for psychotic disorders. Both are found to be associated with increased level of positive symptoms, in particular auditory hallucinations. Our main aim was to investigate the experience and effect of childhood trauma in patients with psychosis from ethnic minorities, hypothesizing that they would report more childhood trauma than the majority and that this would be associated with more current and lifetime hallucinations. METHOD In this cross-sectional study we included 454 patients with a SCID-I DSM-IV diagnosis of non-affective or affective psychotic disorder. Current hallucinations were measured with the Positive and Negative Syndrome Scale (P3; Hallucinatory Behaviour). Lifetime hallucinations were assessed with the SCID-I items: auditory hallucinations, voices commenting and two or more voices conversing. Childhood trauma was assessed with the Childhood Trauma Questionnaire, self-report version. RESULTS Patients from ethnic minority groups (n = 69) reported significantly more childhood trauma, specifically physical abuse/neglect, and sexual abuse. They had significantly more current hallucinatory behaviour and lifetime symptoms of hearing two or more voices conversing. Regression analyses revealed that the presence of childhood trauma mediated the association between ethnic minorities and hallucinations. CONCLUSIONS More childhood trauma in ethnic minorities with psychosis may partially explain findings of more positive symptoms, especially hallucinations, in this group. The association between childhood trauma and these first-rank symptoms may in part explain this groups higher risk of being diagnosed with a schizophrenia-spectrum diagnosis. The findings show the importance of childhood trauma in symptom development in psychosis.

Contribution of oxytocin receptor polymorphisms to amygdala activation in schizophrenia spectrum disorders

Background Oxytocin has been proposed to mediate amygdala dysfunction associated with altered emotion processing in schizophrenia, but the contribution of oxytocin pathway genes is yet to be investigated. Aims To identify potential different contributions of three oxytocin receptor polymorphisms (rs53576, rs237902 and rs2254298) between patients with schizophrenia spectrum disorders (SCZ), affective spectrum disorders (AD) and healthy controls (HC). Method In a total of 346 participants (104 with SCZ, 100 with AD, and 142 HC) underwent genotyping and functional magnetic resonance imaging (fMRI) during an emotional faces matching paradigm. Genetic association analyses were performed to test the possible effects on task-induced BOLD amygdala response to fearful/angry faces. Results In participants with SCZ, the rs237902 G allele was associated with low amygdala activation (left hemisphere: b=−4.99, Bonferroni corrected P=0.04) and interaction analyses showed that this association was disorder specific (left hemisphere: Bonferroni corrected P=0.003; right hemisphere: Bonferroni corrected P=0.03). There were no associations between oxytocin polymorphisms and amygdala activation in the total sample, among AD patients or HC. Conclusions Rs237902 was associated with amygdala activation in response to fearful/angry faces only in patients with SCZ. Our findings indicate that the endogenous oxytocin system could serve as a contributing factor in biological underpinnings of emotion processing and that this contribution is disorder specific. Declaration of interest O.A.A. received speaker’s honoraria from GSK, Otsuka, Lundbeck. Copyright and usage

Serum levels of second-generation antipsychotics are associated with cognitive function in psychotic disorders

Abstract Objectives: Antipsychotics are effective in treating psychosis and mood episodes; however, the effect on cognition is less known. We investigated the association between serum levels of second-generation antipsychotics (SGAs) and cognitive performance in psychosis spectrum disorders in a naturalistic setting. Methods: A total of 495 patients with a DSM-IV Schizophrenia and Other Psychotic Disorders (SCZ, n = 373) or Bipolar Disorder (BD, n = 122) diagnosis treated with olanzapine, quetiapine, aripiprazole or risperidone were tested neuropsychologically with concurrent measurement of the serum concentration of the drug. Linear regression was used for association analyses. Results: Attention was positively associated with the olanzapine concentration (standardised beta (β) coefficient = 0.19, P = .006), and short-term verbal memory and verbal fluency were negatively associated with the quetiapine (β = –0.24, P = .004) and risperidone (β = –0.37, P = .007) concentrations respectively. Conclusions: The present results suggest that SGA serum concentration is associated with better attention (small effect size), and worse verbal memory (small effect size) and verbal fluency (medium effect size). These findings are in line with the notion that SGAs affect aspects of cognitive function, and suggest careful dosing in patients with severe memory and executive problems.

Vitamin D Deficiency Associated With Cognitive Functioning in Psychotic Disorders.

BACKGROUND Cognitive dysfunctions are core features of psychotic disorders with substantial impact on daily functioning. Vitamin D deficiency has been found to be related to cognitive dysfunctions, but the associations between vitamin D deficiency and cognition in persons with a psychotic disorder are largely unknown. METHODS This cross-sectional study included 225 patients with a DSM-IV psychotic disorder consecutively recruited from 2003 to 2014 and 159 randomly selected healthy controls, assessed by a cognitive test battery, a clinical protocol (including Structured Clinical Interview for DSM-IV Axis I Disorders and Positive and Negative Syndrome Scale), and a physical examination including vitamin D measurements. Multiple regression models were performed to evaluate the effect of vitamin D deficiency (defined serum 25-hydroxyvitamin D [25(OH)D] < 25 nmol/L) on key cognitive domains: processing speed, verbal learning, verbal memory, and executive functioning. RESULTS Vitamin D deficiency was significantly associated with decreased processing speed (ie, Digit Symbol Coding) (t = -2.6, P = .01; total model: adjusted R² = 0.40, F6, 374 = 43.8, P < .001) and decreased fluency (ie, verbal fluency) (t = -2.1, P = .04; total model: adjusted R² = 0.35, F6, 373 = 34.2, P < .001) when the results were controlled for age, ethnicity, IQ, patient versus control status, and substance or alcohol abuse. Additional analyses indicated that negative symptoms diluted the association between vitamin D deficiency and processing speed (t = -1.72, P = .09) and verbal fluency (t = -1.35, P = .18) in patients. CONCLUSION The associations between vitamin D deficiency and processing speed and verbal fluency are good arguments for planning large-scale randomized controlled studies in target populations so conclusions can be made about the potential beneficial effect of vitamin D on cognition in psychotic disorders.