No difference in insulin resistance and lipid levels between controls and adolescent subjects who later develop psychosis

Type 2 diabetes and dyslipidemias co-occur frequently with psychoses, but it is not known how common they are in adolescents who later develop psychosis. We investigated waist circumference, blood glucose, lipid and insulin levels and insulin resistance in the Northern Finland 1986 Birth Cohort at the age of 15/16 (N=5410). The Social Insurance Institute register and the Finnish Hospital Discharge Register were used to find the participants who developed psychosis (N=21), and they were compared with other participants. There were no differences in the cardiometabolic variables, suggesting that psychotic episode is not preceded by glucose and lipid metabolism disturbances.     

Inflammatory and cardiometabolic markers at presentation with first episode psychosis and long-term clinical outcomes: A longitudinal study using electronic health records

Approximately one third of patients presenting with a first episode of psychosis need long-term support, but there is a limited understanding of the sociodemographic or biological factors that predict this outcome. We used electronic health records from a naturalistic cohort of consecutive patients referred to an early intervention in psychosis service to address this question. We extracted data on demographic (age, sex, ethnicity and marital status), immune (differential cell count measures and C-reactive protein (CRP)) and metabolic (cholesterol, triglycerides, glucose, glycated haemoglobin, blood pressure, body mass index (BMI)) factors at baseline, and subsequent need for long-term secondary (specialist) psychiatric care. Of 749 patients with outcome data available, 447 (60%) had a good outcome and were discharged to primary care, while 302 (40%) required follow-up by secondary mental health services indicating a worse outcome. The need for ongoing secondary mental healthcare was associated with high triglyceride levels (adjusted odds ratio/OR = 7.32, 95% CI 2.26–28.06), a low basophil:lymphocyte ratio (adjusted OR = 0.14, 95% CI 0.02–0.58), and a high monocyte count (adjusted OR = 2.78, 95% CI 1.02–8.06) at baseline. The associations for baseline basophil (unadjusted OR = 0.27 per SD, 95% CI 0.10–0.62) and platelet counts (unadjusted OR = 2.88, 95% CI 1.29–6.63) attenuated following adjustment for BMI. Baseline CRP levels or BMI were not associated with long-term psychiatric outcomes. In conclusion, we provide evidence that triglyceride levels and several blood cell counts measured at presentation may be clinically useful markers of long-term prognosis for first episode psychosis in clinical settings. These findings will require replication.     

Depression in first episode psychosis: The role of subordination and shame

Depression in early psychosis is linked to poor outcome, relapse and risk of suicide, yet remains poorly understood. This article aims to examine the development of depression in acute and post psychotic phases of first episode psychosis (FEP), and its relationship to persecutors, voices, insight, and recovery. Data were gathered on 92 patients with acute FEP on depression course, severity and experience of positive symptoms, insight and appraisals of illness using validated semi-structured interviews and questionnaires. Measures were repeated at 12 months. Malevolent voices, use of safety behaviours and subordination to persecutors were associated with depression and suicidal behaviour in acute FEP. Loss, Shame, low level continuing positive symptoms and longer duration of untreated psychosis were associated with post psychotic depression. Negative appraisals remained stable despite recovery in other symptom domains. Thus, depression and risk in early psychosis may be propagated by the personal significance and content of positive symptoms experienced. When in recovery, low level symptoms, longer period of illness and negative appraisals are significant factors.     

Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression

Bidirectional relationships between inflammation and metabolic dysfunction may contribute to the pathophysiology of psychiatric illnesses like depression. Metabolic disturbances drive inflammation, which in turn exacerbate metabolic outcomes including insulin resistance. Both inflammatory (e.g. endotoxin, vaccination) and metabolic challenges (e.g. glucose ingestion) have been shown to affect activity and functional connectivity (FC) in brain regions that subserve reward and motor processing. We previously reported relationships between elevated concentrations of endogenous inflammatory markers including C-reactive protein (CRP) and low corticostriatal FC, which correlated with symptoms of anhedonia and motor slowing in major depression (MD). Herein, we examined whether similar relationships were observed between plasma markers related to glucose metabolism (non-fasting concentrations of glucose, insulin, leptin, adiponectin and resistin) in 42 medically-stable, unmedicated MD outpatients who underwent fMRI. A targeted, hypothesis-driven approach was used to assess FC between seeds in subdivisions of the ventral and dorsal striatum and a region in ventromedial prefrontal cortex (VS-vmPFC), which was previously found to correlate with both inflammation and symptoms of anhedonia and motor slowing. Associations between FC and gene expression signatures were also explored. A composite score of all 5 glucose-related markers (with increasing values reflecting higher concentrations) was negatively correlated with both ventral striatum (VS)-vmPFC (r = −0.33, p < 0.05) and dorsal caudal putamen (dcP)-vmPFC (r = −0.51, p < 0.01) FC, and remained significant after adjusting for covariates including body mass index (p < 0.05). Moreover, an interaction between the glucose-related composite score and CRP was observed for these relationships (F[2,33] = 4.3, p < 0.05) whereby significant correlations between the glucose-related metabolic markers and FC was found only in patients with high plasma CRP (>3 mg/L; r = −0.61 to −0.81, p < 0.05). Insulin and resistin were the individual markers most predictive of VS-vmPFC and dcP-mPFC FC, respectively, and insulin, resistin and CRP clustered together and in association with both LV-vmPFC and dcP-vmPFC in principal component analyses. Exploratory whole blood gene expression analyses also confirmed that gene probes negatively associated with FC were enriched for both inflammatory and metabolic pathways (FDR p < 0.05). These results provide preliminary evidence that inflammation and metabolic dysfunction contribute jointly to deficits in reward and motor circuits in MD. Future studies using fasting samples and longitudinal and interventional approaches are required to further elucidate the respective contributions of inflammation and metabolic dysfunction to circuits and symptoms relevant to motivation and motor activity, which may have treatment implications for patients with psychiatric illnesses like depression.     

Severity of psychosis syndrome and change of metabolic abnormality in chronic schizophrenia patients: Severe negative syndrome may be related to a distinct lipid pathophysiology

BackgroundMetabolic abnormality is common among schizophrenia patients. Some metabolic traits were found associated with subgroups of schizophrenia patients.ObjectivesWe examined a possible relationship between metabolic abnormality and psychosis profile in schizophrenia patients.MethodThree hundred and seventy-two chronic schizophrenia patients treated with antipsychotics for more than 2 years were assessed with the Positive and Negative Syndrome Scale. A set of metabolic traits was measured at scheduled checkpoints between October 2004 and September 2006.ResultsMultiple regressions adjusted for sex showed negative correlations between body mass index (BMI) and total score and all subscales; triglycerides (TG) was negatively correlated with total score and negative syndrome, while HDLC was positively correlated with negative syndrome. When sex interaction was concerned, total score was negatively correlated with BMI but not with others; negative syndrome was negatively correlated with BMI and positively with HDLC. No metabolic traits were correlated with positive syndrome or general psychopathology.ConclusionsLoss of body weight is a serious health problem in schizophrenia patients with severe psychosis syndrome, especially the negative syndrome. Schizophrenia patients with severe negative syndrome may have a distinct lipid pathophysiology in comparison with those who were less severe in the domain.     

Routine evaluation in first episode psychosis services: feasibility and results from the MiData project

Background

Early intervention services (EIS) for psychosis are becoming widespread. Structured methods of assessment are advocated in these services, but a consensus is still needed on a package of measures with good psychometric properties that is feasible and reliable for routine use in this setting.

Methods

A computerised assessment package (MiData) was designed to provide clinicians with easy-to-understand feedback about clients’ progress and to allow evaluation of the whole service for both audit and research purposes. Core areas include symptoms, duration of untreated psychosis (DUP), pathways into care, social functioning, and substance misuse at initial intake and annually thereafter.

Results

MiData has been adopted by EIS throughout London and in some other centres. Baseline data are now available regarding 533 first-episode psychosis patients who presented to 8 London teams. The completeness of the data varied across teams and measures, with fullest completion for sociodemographic data (99% on some measures) and poorest for DUP. The average London EIS client is male, single, unemployed and comes from Black or Minority Ethnic group. Most (70%) demonstrated poor social functioning at intake, over a third (38%) reported substance abuse problems and 23% had harmed themselves or others in the previous 6 months.

Conclusions

MiData provides a clinician-friendly system of evaluating first-episode psychosis services but requires further refinement and dedicated resources to improve completion rates. This method of collecting routine data is of use to clinicians, managers, health service researchers and commissioners and potentially it may enable naturalistic comparisons between different models of care.     

Prediction of long-term metabolic effects of olanzapine and risperidone treatment from baseline body mass index in schizophrenia and bipolar disorder

Baseline body mass index (BMI), baseline BMI status (normal, overweight, obese) and early (1 month) BMI increases were tested as predictors of 6- and 12- month increases in glucose and lipid measures in 82 olanzapine (OLZ)- and 78 risperidone (RIS)-treated patients with schizophrenia, schizoaffective disorder, or bipolar disorder who participated in a 12-month randomized, prospective metabolic effects study. Baseline BMI predicted greater fasting glucose and HgbA1c levels at 12 months for both treatments. Early BMI change predicted fasting glucose levels at 6 months, but not HgbA1c or BMI, at either time point. For patients who received no concomitant mood stabilizers, early BMI change predicted 12 month HgbA1c values in the OLZ group, and 6- (but not 12-) month fasting glucose and HgbA1c values in the RIS group. Neither baseline BMI nor early BMI change consistently predicted increases in lipids with either drug. OLZ-treated patients with normal baseline BMI had greater increases in total cholesterol, triglycerides, and non-HDL-cholesterol than those who were overweight or obese. In conclusion, higher baseline BMI predicted adverse glycemic changes after 12 months with OLZ and RIS. Individuals with normal baseline BMI may be most susceptible to OLZ-induced hyperlipidosis. Frequency of metabolic screening should be independent of baseline BMI or rapid increases in BMI.     

Drug and alcohol misuse in first episode psychosis: An observational study

BACKGROUND: There have been very few observational studies of drug and alcohol misuse in first-episode psychosis in the UK. METHOD: Using an observational database of first episode psychosis in Northumberland, a county in Northern England, information on patients aged 16 to 36 years were collected at presentation and annual follow-up between October 1998 and October 2005. Patterns of drug and alcohol misuse were compared using hospitalization as an outcome measure, and violence rates were examined retrospectively. RESULTS: Drug misuse without alcohol misuse was associated with a highly significant increase in hospital days. An alcohol problem, either with or without coexisting drug misuse, was not predictive of increased hospital days. Drug and alcohol misuse together was associated with violence. CONCLUSIONS: This paper lends some support to those Early Intervention in Psychosis (EIP) teams currently advising patients that drug misuse may have a greater impact than alcohol use on the outcome of first-episode psychosis.     

Depression profilers and immuno-metabolic dysregulation: Longitudinal results from the NESDA study

BackgroundMajor depressive disorder (MDD) is linked to higher cardio-metabolic comorbidity that may in part be due to the low-grade inflammation and poorer metabolic health observed in MDD. Heterogeneity of MDD is however large, and immune-inflammatory and metabolic dysregulation is present in only part of the MDD cases. We examined the associations of four depression dimensional profilers (atypical energy-related symptom dimension, melancholic symptom dimension, childhood trauma severity, and anxious distress symptom dimension) with immuno-metabolic outcomes, both cross-sectionally and longitudinally.MethodsThree waves covering a 6-year follow-up (>7000 observations) of the Netherlands Study of Depression and Anxiety (NESDA) were used. Depression profilers were based on the Inventory of Depressive Symptomatology, the Beck Anxiety Inventory, and the Childhood Trauma index. An inflammatory index (based on IL-6 and CRP), a metabolic syndrome index (based on the five metabolic syndrome components), and a combination of these two indices were constructed. Mixed models were used for cross-sectional and longitudinal models, controlling for covariates.ResultsOf the four depression profilers, only the atypical, energy-related symptom dimension showed robust associations with higher scores on the inflammatory, metabolic syndrome and combined inflammatory-metabolic indexes cross-sectionally, as well as at follow-up. The melancholic symptom dimension was associated with lower scores on the metabolic syndrome index both cross-sectionally and longitudinally.ConclusionThe atypical energy-related symptom dimension was linked to poorer immune-inflammatory and metabolic health, while the melancholic symptom dimension was linked to relatively better metabolic health. Persons with high atypical energy-related symptom burden, representing an immuno-metabolic depression, may be the most important group to target in prevention programs for cardiometabolic disease, and may benefit most from treatments targeting immuno-metabolic pathways.     

A five-year longitudinal study of the regional cerebral metabolic changes of a schizophrenic patient from the first episode using Tc-99m HMPAO SPECT

This is a naturalistic study of the relationship between cerebral metabolic activity, clinical symptoms and treatment response in a schizophrenic patient for 5 years from the onset of her illness. Serial technetium-99m-HMPAO brain SPECT was used to measure regional cerebral metabolism. The Cambridge Neurological Inventory and neuropsychological tests (WAIS-R verbal subscales, Wisconsin Card Sorting Test, semantic verbal fluency, logical memory in Weschler Memory Scale) were used for neurocognitive assessment. Under-activity of the left temporal area was observed in the course of patient illness despite remission of the psychotic symptoms. Bilateral prefrontal metabolic under-activity was noted at the emergence of negative symptoms, executive neurocognitive dysfunction and the treatment-resistant state. After response to clozapine, the right prefrontal activity returned to a normal level. Our findings suggested that persistent left temporal under-activity detected by SPECT despite clinical remission may indicate a vulnerability for further relapses and development of a treatment-resistant state. Treatment-resistant state, negative symptoms and executive neurocognitive deficit may involve abnormal prefrontal metabolic activity and can be alleviated in clozapine-responsive patients. Received: 10 August 1998 / Accepted: 7 December 1999     

Caudate volume changes in first episode psychosis parallel the effects of normal aging: a 5-year follow-up study

We investigated whether the caudate nuclei volume (CNV) of 15 first episode psychosis patients increased after 5 years of treatment with either atypical antipsychotics or low doses of typical antipsychotics. Caudate volumes were measured from magnetic resonance imaging (MRI) scans in 15 patients and 10 healthy controls. Both groups demonstrated a significant 9% decline in caudate volume. We were unable to replicate previous reports of caudate enlargement in patients receiving antipsychotic treatment.     

Gene signatures in peripheral blood immune cells related to insulin resistance and low tyrosine metabolism define a sub-type of depression with high CRP and anhedonia

Inflammation and altered glucose metabolism are two pathways implicated in the pathophysiology of major depressive disorder (MDD). We have previously shown that high inflammation as measured by C-reactive protein (CRP) in MDD patients is associated with symptoms of anhedonia, a core symptom of MDD, along with deficits in dopaminergic reward circuitry. Increased inflammation can shift metabolic demand and reprogram cellular energy sources, which may collectively impact the brain and reward processing to contribute to symptoms of anhedonia. To determine whether immunometabolic gene signatures were enriched in immune cells of depressed patients with increased inflammation and anhedonia, we examined whole-blood gene expression microarray (Illumina HumanHT-12) data from unmedicated, medically-stable patients with MDD (n = 93). Patients were considered to have increased inflammation based on High (>3mg/L) versus Low (≤3mg/L) plasma CRP, and further classified as having a self-reported phenotype of High (n = 30, 33rd percentile) versus Low (n = 32, 67th percentile) Anhedonia. Functional enrichment of gene pathways was assessed by Gene Set Enrichment Analysis (GSEA) using the KEGG pathway database. Pathways related to glucose metabolism (insulin signaling, insulin resistance, HIF-1, PI3K/AKT signaling), cancer (e.g., genes related to insulin and PI3K/AKT signaling), and inflammation (B cell, T cell and Fc receptor signaling) were specifically enriched in patients with both High CRP and High Anhedonia (all FDR q < 0.25). Within patients with High CRP in GSEA, the insulin signaling pathway was the top enriched pathway in patients with High versus Low Anhedonia (n = 10 and 9 respectively), which was driven by genes expressed predominantly in monocytes (z = 2.95, p < 0.01). Conversely, within patients with High Anhedonia, in addition to enrichment of immunometabolic pathways, the tyrosine metabolism pathway was also reduced in patients with High versus Low CRP (n = 20 and 10 respectively). Of note, enrichment of immunometabolic pathways was confirmed in complementary linear regression analyses examining pathways associated with a CRP-by-Anhedonia interaction term while controlling for clinical covariates in all patients (n = 93). These results indicate that increased glucose and low tyrosine metabolism define a subset of depressed patients with high inflammation and anhedonia. Enrichment of cancer-related pathways driven by metabolic genes also suggests a shift in immune cell metabolism from oxidative phosphorylation to glycolysis. Together these data suggest that anhedonia in MDD with high CRP involves both immunometabolic shifts and reduced dopamine precursor availability.     

Fronto-temporal disconnectivity and clinical short-term outcome in first episode psychosis: A DTI-tractography study

Determining reliable markers of clinical outcome for psychosis is essential to adjust intervention efforts. White matter alterations exist prior to psychosis onset but its association with clinical outcome in the very early phase of psychosis is currently unknown. In the present study, white matter was assessed by diffusion tensor imaging (DTI) in patients with first episode psychosis (FEP) and healthy controls. Forty-four FEP patients and 30 matched healthy controls completed a DTI scan. The patient group was split in poor (n = 24) and good (n = 20) outcome subgroups based on 6-month clinical data. DTI tractography was used to estimate fractional anisotropy (FA) in the three main tracts connecting frontal and temporal regions (i.e. the cingulum, the superior longitudinal fasciculus and the uncinate fasciculus). The analyses showed selective FA reductions in both the uncinate and the superior longitudinal fasciculi, but not in the cingulum, when comparing FEP patients to healthy controls. FEP subgroup analyses revealed greater white matter changes in these tracts in patients with poor outcome as compared to patients with good outcome. These findings confirm that abnormal fronto-temporal connectivity contributes to the physiopathology of FEP and constitutes an early marker of clinical short-term outcome.     

Psychiatric comorbidity in first episode schizophrenia: a 2 year, longitudinal outcome study

OBJECTIVE: We have previously documented a high prevalence of Axis I psychiatric comorbidity in our patients with first episode psychosis. This study sought to determine the longitudinal impact of Axis I psychiatric comorbidity on patients with first episode schizophrenia (FES) and we hypothesised that patients with psychiatric comorbidity were associated with poorer clinical and functional outcomes. METHOD: One hundred and forty two consecutively hospitalized FES patients were included. Socio-demographic information was obtained and the PANSS, SUMD, GAF, WHOQOL-Bref were used to assess psychopathology, insight, social/occupational functioning and quality of life respectively at baseline and at 6, 12, 18 and 24 months after discharge. RESULTS: Over time and compared with baseline scores, patients with Axis I psychiatric comorbidity (n=46, 32.4%) had significantly less reduction of their PANSS total and subscale scores, less improvement in their awareness of their psychiatric illnesses and symptoms at 12, 18 and 24 months and poorer insight into the consequences of their illness at 18 and 24 months. Poor insight at baseline was correlated positively with PANSS negative symptom subdomain, and negatively with GAF at 24 months. CONCLUSION: Axis I Psychiatric comorbidity was associated with worse prospective outcomes in hospitalized patients with first episode schizophrenia, and this highlights a greater need towards the early recognition and management of these conditions.     

Inflammation in obese children and adolescents: Association with psychosocial stress variables and effects of a lifestyle intervention

Obesity in childhood and adolescence is a complex health issue that has detrimental effects on the physical and psychological health of the youngster, both in the short and long term. A characteristic of obesity is the associated chronic low-grade inflammation which can result in insulin resistance. Previous research suggested that biomarkers referring to such increased inflammation may help in understanding resistance to weight loss. Whether and how psychosocial factors are related with inflammation remains to be proven. The current study consisted of 594 children and adolescents (7–19 years), of whom 480 had follow-up data, who enrolled for a ten-month inpatient multidisciplinary obesity treatment consisting of healthy food routines, physical activities and psychological treatment. The purpose of the study was to explore (1) the relationship between inflammation and psychosocial stress variables (i.e., depressive symptoms, eating behavior, concerns about eating/shape/weight, insecure parent-child attachment) (correlational and multiple regression analysis), (2) whether a lifestyle intervention for obese youngsters results in decreased C-reactive protein (CRP) values (paired t-test) and (3) which psychosocial variables influence this CRP change as indication of treatment success (multiple regression analysis with change in BMI as control variable). Results showed that the psychosocial stress variables emotional eating, external eating and attachment anxiety are related to higher CRP values. Our data further suggested that a lifestyle intervention decreases the CRP values. This significant reduction in blood inflammatory marker was besides being influenced by weight loss also dependent on psychosocial variables, more specific on self-reported attachment avoidance, as this latter was related to less CRP decrease.     

Associations between childhood victimization,inflammatory biomarkers and psychotic phenomena in adolescence: A longitudinal cohort study

Exposure to victimization in childhood has been linked to the development of psychosis. However, little is known about how childhood victimization is translated into biological risk for psychosis. One possibility is via increased inflammation. This study aimed to investigate the association between childhood victimization, psychotic experiences (PEs) in adolescence and inflammatory markers using data from a general population cohort. Participants were 1,419 British-born children followed from birth to age 18 years as part of the Environmental Risk Longitudinal Twin Study. Childhood victimization was measured prospectively using multiple sources from birth to age 12 years. PEs were assessed during private interviews with participants at age 18 years for the period since age 12. Plasma C-reactive protein (CRP), interleukin-6 (IL-6), and soluble urokinase plasminogen activator receptor (suPAR) levels were measured from plasma samples collected from participants at 18 years. Young people with both PEs and childhood victimization were more likely to belong to a group with elevated suPAR, CRP and IL-6 levels at 18 years of age (OR = 3.34, 95% CI 1.69–6.59, p = 0.001) than those with no childhood victimization and without PEs. However, this association was attenuated when adjusted for other risk factors for elevated inflammation at age 18 (OR = 1.94, 95% CI 0.94–4.04, p = 0.075). In contrast, presence of PEs without childhood victimization was not significantly associated with age-18 inflammatory markers and neither was childhood victimization without PEs (all p’s greater than 0.05). The current study highlights that inflammatory dysregulation is mostly present in adolescents reporting PEs who also experienced childhood victimization, though this seemed to be largely due to concurrent inflammation-related risk factors.     

P300 asymmetry and positive symptom severity: a study in the early stage of a first episode of psychosis

The amplitude of the P300 event-related potential (ERP) has been reported to be reduced over left compared to right temporal sites in schizophrenia patients. This left temporal P300 reduction has been associated with positive symptom severity and gray matter reduction in the left superior temporal gyrus. We investigated a group of patients with a first episode of schizophrenia spectrum psychosis and a group of normal controls to verify if P300 amplitude asymmetry already exists around the time of presentation for treatment. Relative to normal control subjects, no P300 asymmetry was found in patients. Nevertheless, P300 asymmetry was correlated with the severity of positive symptoms and worse global functioning (GAF), a good predictor of poor outcome.