Peripheral metabolic state and immune system in first-episode psychosis - A gene expression study with a prospective one-year follow-up.

he excess availability of glucose and lipids can also have an impact on the dynamics of activation and regulation of peripheral immune cellsWe aimed at understanding the correlations between peripheral metabolic state and immune system during the first year in first-episode psychosis (FEP). Patients with FEP (n = 67) and matched controls (n = 38), aged 18-40 years, were met at baseline, 2 and 12 months. Fasting peripheral blood samples were collected. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 178 candidate genes reflecting activation of the immune system. Serum triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol and insulin and plasma glucose (fP-Gluc) were measured. We applied Ingenuity Pathway Analysis (IPA) to visualize enrichment of genes to functional classes. Strength of positive or negative regulation of the disease and functional pathways was deduced from IPA activation Z-score at the three evaluation points. We correlated gene expression with plasma glucose, triglycerids and HDL and LDL, and used hierarchical clustering of the pairwise correlations to identify groups of genes with similar correlation patterns with metabolic markers. In patients, initially, genes associated with the innate immune system response pathways were upregulated, which decreased by 12 months. Furthermore, genes associated with apoptosis and T cell death were downregulated, and genes associated with lipid metabolism were increasingly downregulated by 12 months. The immune activation was thus an acute phase during illness onset. At baseline, after controlling for multiple testing, 31/178 genes correlated positively with fasting glucose levels, and 54/178 genes negatively with triglycerides in patients only. The gene clusters showed patterns of correlations with metabolic markers over time. The results suggest a functional link between peripheral immune system and metabolic state in FEP. Metabolic factors may have had an influence on the initial activation of the innate immune system. Future work is necessary to understand the role of metabolic state in the regulation of immune response in the early phases of psychosis.

Development and implementation of guidelines for the management of depression: a systematic review.

OBJECTIVE: To evaluate the development and implementation of clinical practice guidelines for the management of depression globally. METHODS: We conducted a systematic review of existing guidelines for the management of depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries. FINDINGS: We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence. CONCLUSION: Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes.

Elevated serum chemokine CCL22 levels in first-episode psychosis: associations with symptoms, peripheral immune state and in vivo brain glial cell function.

Several lines of research support immune system dysregulation in psychotic disorders. However, it remains unclear whether the immunological marker alterations are stable and how they associate with brain glial cell function. This longitudinal study aimed at investigating whether peripheral immune functions are altered in the early phases of psychotic disorders, whether the changes are associated with core symptoms, remission, brain glial cell function, and whether they persist in a one-year follow-up. Two independent cohorts comprising in total of 129 first-episode psychosis (FEP) patients and 130 controls were assessed at baseline and at the one-year follow-up. Serum cyto-/chemokines were measured using a 38-plex Luminex assay. The FEP patients showed a marked increase in chemokine CCL22 levels both at baseline (p < 0.0001; Cohen's d = 0.70) and at the 12-month follow-up (p = 0.0007) compared to controls. The group difference remained significant (p = 0.0019) after accounting for relevant covariates including BMI, smoking, and antipsychotic medication. Elevated serum CCL22 levels were significantly associated with hallucinations (ρ = 0.20) and disorganization (ρ = 0.23), and with worse verbal performance (ρ = -0.23). Brain glial cell activity was indexed with positron emission tomography and the translocator protein radiotracer [11C]PBR28 in subgroups of 15 healthy controls and 14 FEP patients with serum CCL22/CCL17 measurements. The distribution volume (VT) of [11C]PBR28 was lower in patients compared to controls (p = 0.026; Cohen's d = 0.94) without regionally specific effects, and was inversely associated with serum CCL22 and CCL17 levels (p = 0.036). Our results do not support the over-active microglia hypothesis of psychosis, but indicate altered CCR4 immune signaling in early psychosis with behavioral correlates possibly mediated through cross-talk between chemokine networks and dysfunctional or a decreased number of glial cells.

Is It Possible to Predict the Future in First-Episode Psychosis?

The outcome of first-episode psychosis (FEP) is highly variable, ranging from early sustained recovery to antipsychotic treatment resistance from the onset of illness. For clinicians, a possibility to predict patient outcomes would be highly valuable for the selection of antipsychotic treatment and in tailoring psychosocial treatments and psychoeducation. This selective review summarizes current knowledge of prognostic markers in FEP. We sought potential outcome predictors from clinical and sociodemographic factors, cognition, brain imaging, genetics, and blood-based biomarkers, and we considered different outcomes, like remission, recovery, physical comorbidities, and suicide risk. Based on the review, it is currently possible to predict the future for FEP patients to some extent. Some clinical features-like the longer duration of untreated psychosis (DUP), poor premorbid adjustment, the insidious mode of onset, the greater severity of negative symptoms, comorbid substance use disorders (SUDs), a history of suicide attempts and suicidal ideation and having non-affective psychosis-are associated with a worse outcome. Of the social and demographic factors, male gender, social disadvantage, neighborhood deprivation, dysfunctional family environment, and ethnicity may be relevant. Treatment non-adherence is a substantial risk factor for relapse, but a small minority of patients with acute onset of FEP and early remission may benefit from antipsychotic discontinuation. Cognitive functioning is associated with functional outcomes. Brain imaging currently has limited utility as an outcome predictor, but this may change with methodological advancements. Polygenic risk scores (PRSs) might be useful as one component of a predictive tool, and pharmacogenetic testing is already available and valuable for patients who have problems in treatment response or with side effects. Most blood-based biomarkers need further validation. None of the currently available predictive markers has adequate sensitivity or specificity used alone. However, personalized treatment of FEP will need predictive tools. We discuss some methodologies, such as machine learning (ML), and tools that could lead to the improved prediction and clinical utility of different prognostic markers in FEP. Combination of different markers in ML models with a user friendly interface, or novel findings from e.g., molecular genetics or neuroimaging, may result in computer-assisted clinical applications in the near future.

Low-grade inflammation in first-episode psychosis is determined by increased waist circumference.

Psychosis is associated with low-grade inflammation as measured by high-sensitivity C-reactive protein (hs-CRP), a risk factor for cardiovascular events and mortality in the general population. We investigated the relationship between hs-CRP and anthropometric and metabolic changes in first-episode psychosis (FEP) during the first treatment year. We recruited 95 FEP patients and 62 controls, and measured longitudinal changes in hs-CRP, weight, waist circumference, insulin resistance, and lipids. We used linear mixed models to analyze the longitudinal relationship between hs-CRP and clinical, anthropometric and metabolic measures. At baseline, patients with FEP had higher levels of insulin resistance, total and low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Baseline weight, waist circumference, hs-CRP, fasting glucose, and high-density lipoprotein cholesterol were similar between patients and controls. Marked increases in anthropometric measures and hs-CRP were observed in FEP during the 12-month follow-up. However, glucose and lipid parameters did not change significantly. In the mixed models, waist circumference and female sex were significant predictors of hs-CRP levels in FEP. Prevention of the early development of abdominal obesity in FEP is crucial, as abdominal obesity is accompanied by chronic low-grade inflammation, which increases further the cardiovascular risk in this vulnerable population.

Mortality in people with psychotic disorders in Finland: A population-based 13-year follow-up study.

OBJECTIVES: We conducted a population based study aiming at finding predictors of mortality in psychotic disorders and evaluating the extent to which sociodemographic, lifestyle and health-related factors explain the excess mortality. METHODS: In a nationally representative sample of Finns aged 30-70years (n=5642), psychotic disorders were diagnosed using structured interviews and medical records in 2000-2001. Information on mortality and causes of death was obtained of those who died by the end of year 2013. Cox proportional hazards models were used to investigate the mortality risk. RESULTS: No people with affective psychoses (n=36) died during the follow-up, thus the analysis was restricted to non-affective psychotic disorders (NAP) (n=106). Adjusting for age and sex, NAP was statistically significantly associated with all-cause mortality (hazard ratio (HR) 2.99, 95% CI 2.03-4.41) and natural-cause mortality (HR 2.81, 95% CI 1.85-4.28). After adjusting for sociodemographic factors, health status, inflammation and smoking, the HR dropped to 2.11 (95% CI 1.10-4.05) for all-cause and to 1.98 (95% CI 0.94-4.16) for natural-cause mortality. Within the NAP group, antipsychotic use at baseline was associated with reduced HR for natural-cause mortality (HR 0.25, 95% CI 0.07-0.96), and smoking with increased HR (HR 3.54, 95% CI 1.07-11.69). CONCLUSIONS: The elevated mortality risk in people with NAP is only partly explained by socioeconomic factors, lifestyle, cardio-metabolic comorbidities and inflammation. Smoking cessation should be prioritized in treatment of psychotic disorders. More research is needed on the quality of treatment of somatic diseases in people with psychotic disorders.

Diabetes and Schizophrenia.

People with schizophrenia have 2- to 5-fold higher risk of type 2 diabetes than the general population. The traditional risk factors for type 2 diabetes, especially obesity, poor diet, and sedentary lifestyle, are common in people with schizophrenia already early in the course of illness. People with schizophrenia also often have low socioeconomic status and income, which affects their possibilities to make healthy lifestyle choices. Antipsychotic medications increase the risk of type 2 diabetes both directly by affecting insulin sensitivity and indirectly by causing weight gain. Lifestyle modification interventions for prevention of diabetes should be an integral part of treatment of patients with schizophrenia. In the treatment of type 2 diabetes in patients with schizophrenia, communication and collaboration between medical care and psychiatric treatment providers are essential.

Early insulin resistance predicts weight gain and waist circumference increase in first-episode psychosis--A one year follow-up study.

First-episode psychosis (FEP) is associated with weight gain during the first year of treatment, and risk of abdominal obesity is particularly increased. To identify early risk markers of weight gain and abdominal obesity, we investigated baseline metabolic differences in 60 FEP patients and 27 controls, and longitudinal changes during the first year of treatment in patients. Compared to controls at baseline, patients had higher low-density lipoprotein, triglyceride and apolipoprotein B levels, and lower levels of high-density lipoprotein and apolipoprotein A-I but no difference in body mass index or waist circumference. At 12-month follow-up, 60.6% of patients were overweight or obese and 58.8% had abdominal obesity. No significant increase during follow-up was seen in markers of glucose and lipid metabolism or blood pressure, but increase in C-reactive protein between baseline and 12-month follow-up was statistically significant. Weight increase was predicted by baseline insulin resistance and olanzapine use, while increase in waist circumference was predicted by baseline insulin resistance only. In conclusion, insulin resistance may be an early marker of increased vulnerability to weight gain and abdominal obesity in young adults with FEP. Olanzapine should be avoided as a first-line treatment in FEP due to the substantial weight increase it causes. In addition, the increase in the prevalence of overweight and abdominal obesity was accompanied by the emergence of low-grade systemic inflammation.