Erlend Strand Gardsjord

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.

Subjective quality of life in first-episode psychosis. A ten year follow-up study

UNLABELLED Subjective quality of life (S-QoL) is an important outcome measure in first episode psychosis (FEP). The aims of this study were to describe S-QoL-development the first 10-years in FEP patients and to identify predictors of this development. METHODS A representative sample of 272 patients with a first episode psychotic disorder was included from 1997 through 2000. At 10 year follow-up 186 patients participated. QoL was measured by the Lehmans Quality of Life Interview. Linear mixed model analyses were performed to investigate longitudinal effects of baseline psychiatric symptoms and socio-economic variables and the effects of changes in the same variables on S-QoL-development. RESULTS S-QoL improved significantly over the follow-up period. More contact with family and a better financial situation at baseline had a positive and longstanding effect on S-QoL-development, but changes in these variables were not associated with S-QoL-development. Higher depressive symptoms and less daily activities at baseline both had a negative independent effect, but a positive interaction effect with time on S-QoL-development indicating that the independent negative effect diminished over time. In the change analysis, increased daily activities and a decrease in depressive symptoms were associated with a positive S-QoL-development. CONCLUSIONS Treatment of depressive symptoms and measures aimed at increasing daily activities seem important to improve S-QoL in patients with psychosis. More contact with family and a better financial situation at baseline have a long-standing effect on S-QoL-development in FEP patients.

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.

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.

Serum level of venlafaxine is associated with better memory in psychotic disorders.

Cognitive impairment is a core feature of psychosis spectrum disorders. Antipsychotics have at best small positive effects on cognitive performance. There is a lack of knowledge regarding the effects of antidepressants on cognitive functioning in these disorders. In the present study cognitive performance was investigated in relation to serum levels of antidepressants in persons with bipolar disorder and schizophrenia. Serum concentrations of escitalopram, citalopram and venlafaxine plus O-desmethylvenlafaxine were measured in a total of 187 participants with bipolar disorder (N=74) or schizophrenia spectrum disorders (N=113), and analyzed in relation to neuropsychological tests performance of verbal learning, verbal memory, attention, working memory, executive functioning and processing speed. Analyses were performed using linear regression adjusting for a range of confounders. There was a significant positive association between the serum level of venlafaxine plus O-desmethylvenlafaxine and verbal memory (immediate recall: Logical Memory Test immediate recall [p=0.015], and long term delayed recall: Logical Memory Test delayed recall [p=0.011]). No significant associations were seen between citalopram or escitalopram and verbal memory. There were no significant associations between the tested antidepressants and verbal learning, attention, working memory, executive functioning, or processing speed. Venlafaxine seem to be associated with better verbal memory in bipolar disorder and schizophrenia. This suggests a possible beneficial role of certain antidepressants on cognitive dysfunction, which may have clinical implications and provide insight into underlying pathophysiology. However, the current findings should be replicated in independent samples.

Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder

The Wnt signaling pathway plays a crucial role in neurodevelopment and in regulating the function and structure of the adult nervous system. Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with evidence of subtle neurodevelopmental, structural and functional neuronal abnormalities. We aimed to elucidate the role of aberrant regulation of the Wnt system in these disorders by evaluating plasma levels of secreted Wnt modulators in patients (SCZ = 551 and BD = 246) and healthy controls (HCs = 639) using enzyme immune-assay. We also investigated the expression of 141 Wnt-related genes in whole blood in a subsample (SCZ = 338, BD = 241, and HCs = 263) using microarray analysis. Both SCZ and BD had dysregulated mRNA expression of Wnt-related genes favoring attenuated canonical (beta-catenin-dependent) signaling, and there were also indices of enhanced non-canonical Wnt signaling. In particular, FZD7, which may activate all Wnt pathways, but favors non-canonical signaling, and NFATc3, a downstream transcription factor and readout of the non-canonical Wnt/Ca2+ pathway, were significantly increased in SCZ and BD (p < 3 × 10−4). Furthermore, patients had lower plasma levels of soluble dickkopf 1 and sclerostin (p < 0.01) compared with HC. Our findings suggest that SCZ and BD are characterized by abnormal Wnt gene expression and plasma protein levels, and we propose that drugs targeting the Wnt pathway may have a role in the treatment of severe mental disorders.

Is going into stable symptomatic remission associated with a more positive development of life satisfaction? A 10-year follow-up study of first episode psychosis

BACKGROUND Quality of life is an important outcome measure for patients with psychosis. We investigated whether going into stable symptomatic remission is associated with a more positive development of subjective quality of life (S-QoL) and if different patient characteristics are associated with S-QoL depending on remission status. METHODS Three hundred and one patients with a first-episode psychosis were included at baseline. At 10-year follow-up 186 were reassessed. QoL was assessed by Lehmans Quality of Life Interview. Remission was defined according to criteria proposed by the Remission in Schizophrenia Working Group. One-way ANOVA, mixed model analysis, bivariate correlations and multiple regression analyses were performed. RESULTS Patients going into stable symptomatic remission showed a more positive S-QoL-development over the follow-up period and reported higher life satisfaction at 10-year follow-up compared to non-remission. At 10-year follow-up, depressive symptoms and alcohol abuse or dependence explained a significant amount of variance in S-QoL among patients in remission. Among patients in non-remission, PANSS excitative component explained a significant amount of variance in S-QoL. All significant effects were negative. CONCLUSIONS Stable symptomatic remission is associated with a more positive development of overall life satisfaction. Furthermore, different symptoms influence life satisfaction depending on status of remission. This has important clinical implications. While patients in remission might need treatment for depressive symptoms to increase S-QoL, in non-remission measures aiming to decrease hostility and uncooperativeness should be part of the treatment approach. Alcohol problems should be treated regardless of remission status.

Side effect burden of antipsychotic drugs in real life – Impact of gender and polypharmacy

Background: Antipsychotic‐associated side effects are well known and represent a significant treatment challenge. Still, few large studies have investigated the overall side effect burden of antipsychotics in real‐life settings. Objective: To describe the occurrence of side effects and perceived burden of antipsychotics in a large naturalistic sample, taking polypharmacy and patient characteristics into account. Method: Patients (n = 1087) with psychotic disorders were assessed for side effects using the Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale in addition to assessment of clinical and pharmacological data. Statistical analyses were performed controlling for possible confounding factors. Results: Use of antipsychotics showed significant associations to neurologic and sexual symptoms, sedation and weight gain, and > 75% of antipsychotics‐users reported side effects. More side effects were observed in patients using several antipsychotics (p = 0.002), with increasing total dose (p = 0.021) and with antipsychotics in combinations with other psychotropic drugs. Patients and investigators evaluated the side effect burden differently, particularly related to severity, gender and antipsychotics dose. Twice as many females described side effect burden as severe (p = 0.004). Conclusion: Patients with psychotic disorders have a high occurrence of symptoms associated with use of antipsychotics, and polypharmacy and female gender are seemingly risk factors for reporting a severe side effect burden. Due to the cross‐sectional design evaluation of causality is tentative, and these findings should be further investigated in prospective studies. HighlightsMore side effects were reported with increasing antipsychotic drug quantity and in combination with other psychotropic drugs.Patients and investigators evaluated the side effect burden differently regarding severity, gender and dose of antipsychotics.A gender difference in reporting of several specific side effects was found.

Persistent increase in TNF and IL-1 markers in severe mental disorders suggests trait-related inflammation: a one year follow-up study

We evaluated if plasma levels of inflammatory markers are persistently altered in severe mental disorders with psychotic symptoms or associated with state characteristics in a longitudinal study.

Attenuated Notch signaling in schizophrenia and bipolar disorder

The Notch signaling pathway plays a crucial role in neurodevelopment and in adult brain homeostasis. We aimed to further investigate Notch pathway activity in bipolar disorder (BD) and schizophrenia (SCZ) by conducting a pathway analysis. We measured plasma levels of Notch ligands (DLL1 and DLK1) using enzyme immunoassays in a large sample of patients (SCZ n = 551, BD n = 246) and healthy controls (HC n = 639). We also determined Notch pathway related gene expression levels by microarray analyses from whole blood in a subsample (SCZ n = 338, BD n = 241 and HC n = 263). We found significantly elevated Notch ligand levels in plasma in both SCZ and BD compared to HC. Significant gene expression findings included increased levels of RFNG and KAT2B (p < 0.001), and decreased levels of PSEN1 and CREBBP in both patient groups (p < 0.001). RBPJ was significantly lower in SCZ vs HC (p < 0.001), and patients using lithium had higher levels of RBPJ (p < 0.001). We provide evidence of altered Notch signaling in both SCZ and BD compared to HC, and suggest that Notch signaling pathway may be disturbed in these disorders. Lithium may ameliorate aberrant Notch signaling. We propose that drugs targeting Notch pathway could be relevant in the treatment of psychotic disorders.