Laura Ortega

Increased serum interleukin-6 levels in early stages of psychosis: Associations with at-risk mental states and the severity of psychotic symptoms

Schizophrenia patients experience activated inflammatory responses, but little is known about the presence of such inflammatory processes at or prior to disease onset. We measured interleukin-6 (IL-6) and C-reactive protein (CRP) serum levels and plasma fibrinogen in 17 at-risk mental state (ARMS) subjects, 77 patients with psychotic disorder (PD) and 25 healthy control subjects (HC). ARMS subjects were followed-up, and transition to psychosis was registered. IL6 rs1800795 SNP was genotyped, as IL-6 levels may be influenced by this genetic variant. We did not observe significant differences in the IL6 rs1800795 SNP genotype frequencies between the groups. ARMS subjects exhibited significantly higher IL-6 levels than did controls (p=0.019). In subjects not taking cannabis, we found that patients diagnosed with ARMS or PD exhibited increased IL-6 levels when compared with HC (p=0.004). In both ARMS and PD subjects, IL-6 levels were positively associated with negative symptoms. However, with respect to positive psychotic symptoms, a different relationship was observed in the ARMS and PD groups (positive relationship in ARMS; negative relationship in PD). These findings could not be attributed to confounding variables, including gender, body mass index (BMI), tobacco consumption or the rs1800795 genotype. Six of 17 ARMS subjects (35%) exhibited a transition to psychosis during the follow-up period of 26 months. ARMS subjects who developed psychosis exhibited increased median IL-6 levels compared with those who did not transition (0.61 vs. 0.35pg/mL). However, this difference was not statistically significant, which could be explained by a lack of statistical power due to the small sample size. Our results suggest that IL-6 may be a biomarker for early psychotic symptoms; however, further studies in larger samples are needed to confirm this result.

Stress biomarkers as predictors of transition to psychosis in at-risk mental states: Roles for cortisol, prolactin and albumin

Stress and inflammation are thought to play a role in the risk of developing a psychotic disorder. We aimed to identify stress-related biomarkers for psychosis transition in help-seeking individuals with an at-risk mental state (ARMS). We studied 39 ARMS subjects who were attending an Early Intervention Service. We included a control group of 44 healthy subjects (HS) matched by sex and age. Stressful life events and perceived stress were assessed. Stress-related biomarkers were determined in serum (cortisol, prolactin, C-reactive protein and albumin), plasma (fibrinogen) or saliva (morning cortisol, cortisol awakening response). All ARMS were followed-up at our Unit for at least one year. We divided the ARMS group into two subgroups based on the development of a psychotic disorder (ARMS-P, N = 10) or not (ARMS-NP, N = 29). ARMS-P reported more stressful life events and perceived stress than HS and ARMS-NP groups. In relation to baseline stress biomarkers, ARMS-P subjects had increased prolactin and lower albumin levels in serum, when compared to ARMS-NP and HS groups. These results did not change when repeated in a subsample of antipsychotic-naïve ARMS subjects. We also found significant differences between groups in the cortisol secretion after awakening. In a multinomial logistic regression adjusting for age, sex and life stress, prolactin was a predictor of psychosis transition whereas albumin levels had a protective effect. Our study underscores the role of stress and stress-related biomarkers (cortisol awakening response, prolactin and albumin) in the pathogenesis of psychosis.

Unhealthy lifestyle in early psychoses: The role of life stress and the hypothalamic–pituitary–adrenal axis

An unhealthy lifestyle is thought to contribute to the metabolic syndrome in subjects with psychoses. In the present study we aimed to study whether life stress or cortisol measures may influence dietary patterns in subjects with early stages of psychoses. We studied 81 subjects with early psychoses (65 subjects with a psychotic disorder [PD] and <5 years of illness; 16 subjects at risk for psychosis [high-risk, HR]) and a control group of 25 healthy subjects (HS). Dietary habits were examined by a dietician, who registered food intake (24h recall). Physical activity was assessed by validated questionnaire. Life stress was assessed with Holmes-Rahe Social Readjustment Scale. Fasting morning salivary and plasma cortisol levels were determined. We found that PD and HR reported an unhealthier lifestyle with more smoking, reduced physical activity and poorer dietary habits. HR reported increased intake of calories and saturated fatty acids and reduced protein consumption, when compared to HS. Life stress was a predictor of these adverse behaviours, although we found opposite associations in HR and PD. Life stress was associated with increased intake of refined sugar in PD and decreased intake in HR and HS. Salivary cortisol was related to increased intake of saturated fat only in HR subjects, but cortisol levels in plasma or saliva were not associated with other dietary habits or obesity measures (BMI, waist circumference). Our study suggests that unhealthy diet in early psychoses is influenced by stress, but our data do not support this effect being mediated by hypercortisolism. Future preventive interventions in psychosis may target dietary habits, particularly for those who are at risk for psychosis.

Changes in prolactin levels and sexual function in young psychotic patients after switching from long-acting injectable risperidone to paliperidone palmitate.

Hyperprolactinaemia is a significant side effect of antipsychotic medications and may cause sexual dysfunction. The aim of our study was to assess the effect of switching from long-acting injectable (LAI) risperidone to paliperidone palmitate (PP) on sexual function and prolactin levels in patients with psychosis. We carried out a prospective observational study during a 3-month period that involved 11 patients with psychosis treated with risperidone-LAI who suffered from hyperprolactinaemia and who were then switched to PP. Two assessments were completed: the first one before the switch and the second one 3 months after the switch. These assessments measured sexual function using the Arizona Sexual Experience Scale and assessed prolactin levels. Our results showed a significant decrease in serum prolactin levels (P=0.041). We observed a four-fold reduction in clinically significant sexual dysfunction that is suggestive of benefit, although the sample size is too small to be sure. Our study suggests that prolactin levels seem to decrease after switching from risperidone-LAI to PP in patients with a psychotic disorder.

Increased Prolactin Levels Are Associated with Impaired Processing Speed in Subjects with Early Psychosis

Hyperprolactinaemia, a common side effect of some antipsychotic drugs, is also present in drug-naïve psychotic patients and subjects at risk for psychosis. Recent studies in non-psychiatric populations suggest that increased prolactin may have negative effects on cognition. The aim of our study was to explore whether high plasma prolactin levels are associated with poorer cognitive functioning in subjects with early psychoses. We studied 107 participants: 29 healthy subjects and 78 subjects with an early psychosis (55 psychotic disorders with <3 years of illness, 23 high-risk subjects). Cognitive assessment was performed with the MATRICS Cognitive Consensus Cognitive Battery, and prolactin levels were determined as well as total cortisol levels in plasma. Psychopathological status was assessed and the use of psychopharmacological treatments (antipsychotics, antidepressants, benzodiazepines) recorded. Prolactin levels were negatively associated with cognitive performance in processing speed, in patients with a psychotic disorder and high-risk subjects. In the latter group, increased prolactin levels were also associated with impaired reasoning and problem solving and poorer general cognition. In a multiple linear regression analysis conducted in both high-risk and psychotic patients, controlling for potential confounders, prolactin and benzodiazepines were independently related to poorer cognitive performance in the speed of processing domain. A mediation analysis showed that both prolactin and benzodiazepine treatment act as mediators of the relationship between risperidone/paliperidone treatment and speed of processing. These results suggest that increased prolactin levels are associated with impaired processing speed in early psychosis. If these results are confirmed in future studies, strategies targeting reduction of prolactin levels may improve cognition in this population.

Gene-environment interaction between the brain-derived neurotrophic factor Val66Met polymorphism, psychosocial stress and dietary intake in early psychosis

The brain‐derived neurotrophic factor (BDNF) is a major participant in the regulation of food intake and may play a role in the regulation of the stress response. We aimed to investigate whether there is a gene‐environment interaction in the relationship between stress and BDNF Val66Met polymorphism in relation to dietary patterns in a sample of subjects with early psychosis.

The relationship between antidepressant treatment and inflammatory markers in early psychosis: preliminary results

Dear Editor, Several studies have reported increased blood and CNS concentrations of inflammatory cytokines in patients with schizophrenia (Potvin et al. 2008; Miller et al. 2011). Recently, it has been proposed that antidepressants may possess central and peripheral anti-inflammatory properties (Daniele et al. 2015). Hereof, specific serotonin reuptake inhibitors (SSRIs) decrease peripheral levels of proinflammatory mediators IL-1β, CRP, and possibly IL-6 in patients with major depression (Hannestad et al. 2011; Hiles et al. 2012). IL-6 induces acute-phase proteins such as Creactive protein (CRP) and fibrinogen. In a recent meta-analysis, IL-6 was significantly increased in acutely relapsed inpatients and in patients experiencing their first episode of psychosis, suggesting a possible state and trait-related marker association in schizophrenia (Miller et al. 2011). Likewise, elevated serum CRP and plasma fibrinogen levels have been reported in schizophrenia (Miller et al. 2014; Ding et al. 2015) and major depressive disorder (MDD) patients (WiumAndersen et al. 2013b). Recently, abnormal hs-CRP levels (>3 mg/L) were associated with antidepressant treatment in non-depressed stable schizophrenia patients, with an illness duration of approximately 10 years (Fond et al. 2016). Although depressive symptoms are highly prevalent (17– 83 %) among first-episode psychosis patients (Sönmez et al. 2014), only one study has explored the use of adjunctive antidepressants in prodromal schizophrenia patients, reporting improved medication compliance, reduced positive symptoms, and no transitions to psychosis in the antidepressanttreated patients compared with a 45 % transition rate in the non-antidepressant-treated group (Cornblatt et al. 2007). Thus, antidepressants may be an optimal treatment strategy in prodromal stages, by lowering the vulnerability to illness through the reduction of trigger states (e.g., stress, anxiety, and depression). There is scarce information about the association between depressive symptoms and inflammatory markers in patients with prodromal schizophrenia. Moreover, it is not known whether antidepressant treatment reduces the levels of inflammatory markers in these patients. Given the hypothesis that antidepressant treatment is associated with a reduction in the levels of inflammatory markers, we explored this relationship in patients with a psychotic disorder at the early stages of the illness. We conducted a cross-sectional study with 77 clinically stable early psychosis (EP) patients and 25 healthy controls (HC) as described previously (Stojanovic et al. 2014). The DSM-IV diagnoses for EP patients were as follows: schizophreniform disorder (n = 19), schizophrenia (n = 12), schizoaffective disorder (n = 10), and psychotic disorder not otherwise specified (n = 36). EP patients were divided into Electronic supplementary material The online version of this article (doi:10.1007/s00213-016-4413-8) contains supplementary material, which is available to authorized users.

P.4.012 Effects of second generation antipsychotics on cognitive domains measured with the Matrics Consensus Cognitive Battery in early psychoses

We included 54 subjects (46.3% female patients; main age 24.5 [standard deviation= 5.2]) with a psychotic disorder with a duration of illness <5 years, attending the Early Psychosis Program from Reus (Tarragona, Spain). A structured clinical interview (Schedules for Clinical Assessment in Neuropsychiatry, SCAN) was used to obtain a clinical diagnosis. Severity of psychotic symptoms was assessed with the PANSS. The MATRICS Consensus Cognitive Battery (MCCB)[3] was administered to evaluate cognitive function in all patients. This battery includes ten neuropsychological tests to assess seven cognitive domains commonly examined in studies of schizophrenia (Speed of Processing [SOP], Attention/Vigilance [AV], Working Memory, Verbal learning, Visual Learning, Reasoning and Problem Solving [RPS] and social Cognition) and the Overall Composite Score. Current antipsychotic treatment was requested. Biperden and benzodiazepine (diazepam equivalents) doses were also registered.