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Perceived ethnic discrimination (PED) is thought to underlie increased prevalence of depressed mood in ethnic minorities. Depression is associated with increased sympathetic and decreased parasympathetic activity. We investigated a biopsychosocial model linking PED, disrupted sympathovagal balance and depressed mood. Baseline data of HELIUS, a cohort study on health among a multi-ethnic population, was used. Heart rate variability (HRV), baroreflex sensitivity (BRS), PED (evaluated with the Everyday Discrimination Scale) and presence of depressed mood (evaluated with the Patient Health Questionnaire-9) were assessed. Associations of PED, HRV/BRS and depressed mood were analyzed with linear and logistic regression analyses. Mediation of the association of PED and depressed mood by HRV/BRS was assessed in a potential outcomes model and four steps mediation analysis. Of 9492 included participants, 14.7% fulfilled criteria for depressed mood. Higher PED was associated with depressed mood (P

Background Recent paradigm shifts suggest that psychopathology manifests through dynamic interactions between individual symptoms. Aims To investigate the longitudinal relationships between symptoms in a transdiagnostic sample of patients with psychiatric disorders. Method A two-wave, cross-lagged panel network model of 15 nodes representing symptoms of depression, (social) anxiety and attenuated psychotic symptoms was estimated, using baseline and 1-year follow-up data of 222 individuals with psychiatric disorders. Centrality indices were calculated to determine important predictors and outcomes. Results Our results demonstrated that the strongest relationships in the network were between (a) more suicidal ideation predicting more negative self-view, and (b) autoregressive relationships of social anxiety symptoms positively reinforcing themselves. Negative self-view was the most predictable node in the network as it had the highest ‘in-expected influence’ centrality, and may be an important transdiagnostic outcome symptom. Conclusions The results give insight into longitudinal interactions between symptoms, which interact in ways that do not adhere to broader diagnostic categories. Our results suggest that self-view can also be a transdiagnostic outcome of psychopathology rather than just a predictor, as is normally posited, and may especially have an important relationship with suicidal ideation. Overall, our study demonstrates the dynamic complexity of psychopathology, and further supports the importance of investigating symptom interactions of different psychopathological dimensions over time and across disorders.

Objective: Life expectancy in patients suffering from affective disorders is considerably diminished. We investigated whether skin autofluorescence (SAF), indicating concentration of advanced glycation end products in the skin and oxidative stress, mediates the association between affective disorders and excess mortality. Methods: Included were 81,041 participants of the Lifelines cohort study. Presence of major depressive disorder, dysthymia, generalised anxiety disorder, panic disorder or social phobia was assessed with the Mini-International Neuropsychiatric Interview. SAF was assessed as mediator in Cox proportional hazards models for all-cause or natural-cause mortality. Results: Mortality was increased in cases with major depression compared to controls (36.4 vs. 22.5 per 100,000 person years). Partial mediation by SAF of the association between affective disorders and mortality was shown (9.0-10.5%, P

BackgroundThis meta-analysis on peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder (MDD) examined which compounds change following psychopharmacological treatment.MethodsThe Embase, PubMed and PsycINFO databases were systematically searched for longitudinal studies reporting measurements of blood compounds in drug-naïve first-episode schizophrenia or MDD.ResultsFor this random-effects meta-analysis, we retrieved a total of 31 studies comprising 1818 schizophrenia patients, and 14 studies comprising 469 MDD patients. Brain-derived neurotrophic factor (BDNF) increased following treatment in schizophrenia (Hedges' g (g): 0.55; 95% confidence interval (CI) 0.39–0.70; p < 0.001) and MDD (g: 0.51; CI 0.06–0.96; p = 0.027). Interleukin (IL)-6 levels decreased in schizophrenia (g: −0.48; CI −0.85 to −0.11; p = 0.011), and for MDD a trend of decreased IL-6 levels was observed (g: −0.39; CI −0.87 to 0.09; p = 0.115). Tumor necrosis factor alpha (TNFα) also decreased in schizophrenia (g: −0.34; CI −0.68 to −0.01; p = 0.047) and in MDD (g: −1.02; CI −1.79 to −0.25; p = 0.009). Fasting glucose levels increased only in schizophrenia (g: 0.26; CI 0.07–0.44; p = 0.007), but not in MDD. No changes were found for C-reactive protein, IL-1β, IL-2 and IL-4.ConclusionsPsychopharmacological treatment has modulating effects on BDNF and TNFα in drug-naïve first-episode patients with either schizophrenia or MDD. These findings support efforts for further research into transdiagnostic preventive strategies and augmentation therapy for those with immune dysfunctions.

Background: Oxidative stress may be a mechanistic link between affective disorders (depressive and anxiety disorders) and somatic disease. Advanced glycation end products are produced under the influence of oxidative stress and in the skin (measured by skin autofluorescence [SAF]) serve as marker for cumulative oxidative stress. Aim of study was to determine whether SAF is associated with presence of affective disorders. Methods: Participants in the Lifelines cohort study who had completed the Mini-International Neuropsychiatric Interview for affective disorders and a SAF-measurement were included. Cross-sectional associations between SAF and presence of the following psychiatric disorders were investigated through logistic regression analyses adjusted for sociodemographic factors, cardiometabolic parameters, and somatic morbidities: major depressive disorder, dysthymia, generalised anxiety disorder, panic disorder or social phobia. Results: Of 81,041 included participants (41.7% male, aged 18–91 years), 6676 (8.2%) were cases with an affective disorder. SAF was associated with presence of affective disorders (OR=1.09 [95%CI 1.07–1.12], P

Importance: Schizophrenia and major depressive disorder (MDD) are associated with increased risks of immunologic disease and metabolic syndrome. It is unclear to what extent growth, immune or glucose dysregulations are similarly present in these disorders without the influence of treatment or chronicity. Objective: To conduct a meta-analysis investigating whether there are altered peripheral growth, immune or glucose metabolism compounds in drug-naïve first-episode patients with schizophrenia or MDD compared with controls. Data sources and study selection: Case-control studies reporting compound measures in drug-naïve first-episode patients with schizophrenia or MDD compared with controls in the Embase, PubMed and PsycINFO databases. Data extraction and synthesis: Two independent authors extracted data for a random-effects meta-analysis. Main outcomes and measures: Peripheral growth, immune or glucose metabolism compounds in schizophrenia or MDD compared with controls. Standardized mean differences were quantified with Hedges’ g (g). Results: 74 studies were retrieved comprising 3453 drug-naïve first-episode schizophrenia patients and 4152 controls, and 29 studies were retrieved comprising 1095 drug-naïve first-episode MDD patients and 1399 controls. Growth factors: brain-derived neurotrophic factor (BDNF) (g = -0.77, P < .001) and nerve growth factor (NGF) (g = -2.51, P = .03) were decreased in schizophrenia. For MDD, we observed a trend toward decreased BDNF (g = −0.47, P = .19) and NGF (g = −0.33, P = .08) levels, and elevated vascular endothelial growth factor levels (g = 0.40, P = .03). Immune factors: interleukin (IL)-6 (g = 0.95, P < .001), IL-8 (g = 0.59, P = .001) and tumor necrosis factor alpha (TNFα) (g = 0.48, P = .002) were elevated in schizophrenia. For C-reactive protein (CRP) (g = 0.57, P = .09), IL-4 (g = 0.44, P = .10) and interferon gamma (g = 0.33, P = .11) we observed a trend toward elevated levels in schizophrenia. In MDD, IL-6 (g = 0.62, P = .007), TNFα (g = 1.21, P < .001), CRP (g = 0.53, P < .001), IL-1β (g = 1.52, P = .009) and IL-2 (g = 4.41, P = .04) were elevated, whereas IL-8 (g = −0.84, P = .01) was decreased. The fasting glucose metabolism factors glucose (g = 0.24, P = .003) and insulin (g = 0.38, P = .003) were elevated in schizophrenia. Conclusions and relevance: Both schizophrenia and MDD show alterations in growth and immune factors from disease onset. An altered glucose metabolism seems to be present from onset in schizophrenia. These findings support efforts for further research into transdiagnostic preventive strategies and augmentation therapy for those with immune or metabolic dysfunctions.

IMPORTANCE: The parasite Toxoplasma gondii has been associated with behavioral alterations and psychiatric disorders. Studies investigating neurocognition in people with T gondii infection have reported varying results. To systematically analyze these findings, a meta-analysis evaluating cognitive function in healthy people with and without T gondii seropositivity is needed. OBJECTIVE: To assess whether and to what extent T gondii seropositivity is associated with cognitive function in otherwise healthy people. DATA SOURCES: A systematic search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. A systematic search of PubMed, MEDLINE, Web of Science, PsycInfo, and Embase was performed to identify studies from database inception to June 7, 2019, that analyzed cognitive function among healthy participants with available data on T gondii seropositivity. Search terms included toxoplasmosis, neurotoxoplasmosis, Toxoplasma gondii, cognition disorder, neuropsychological, and psychomotor performance. STUDY SELECTION: Studies that performed cognitive assessment and analyzed T gondii seroprevalence among otherwise healthy participants were included. DATA EXTRACTION AND SYNTHESIS: Two researchers independently extracted data from published articles; if needed, authors were contacted to provide additional data. Quantitative syntheses were performed in predefined cognitive domains when 4 independent data sets per domain were available. Study quality, heterogeneity, and publication bias were assessed. MAIN OUTCOMES AND MEASURES: Performance on neuropsychological tests measuring cognitive function. RESULTS: The systematic search yielded 1954 records. After removal of 533 duplicates, an additional 1363 records were excluded based on a review of titles and abstracts. A total of 58 full-text articles were assessed for eligibility (including reference list screening); 45 articles were excluded because they lacked important data or did not meet study inclusion or reference list criteria. The remaining 13 studies comprising 13 289 healthy participants (mean [SD] age, 46.7 [16.0] years; 6586 men [49.6%]) with and without T gondii seropositivity were included in the meta-analysis. Participants without T gondii seropositivity had favorable functioning in 4 cognitive domains: processing speed (standardized mean difference [SMD], 0.12; 95% CI, 0.05-0.19; P = .001), working memory (SMD, 0.16; 95% CI, 0.06-0.26; P = .002), short-term verbal memory (SMD, 0.18; 95% CI, 0.09-0.27; P

Background: Skin autofluorescence (SAF), indicating concentration of advanced glycation end products in the skin and oxidative stress, is cross-sectionally associated with affective disorders. Prospective studies of oxidative stress markers will help to clarify the pathophysiological role of oxidative stress. Methods: Data of a population-based cohort study were used. Presence of major depressive disorder, dysthymia, generalised anxiety disorder, panic disorder or social phobia was assessed at baseline and at 5-year follow-up with the Mini-International Neuropsychiatric Interview. Associations between SAF at baseline and incidence and persistence/recurrence of affective disorders were assessed with logistic regression. Results: Of 43,267 participants with no disorder at baseline, 2885 (6.7%) developed an incident disorder during follow-up. In 1360 of 3648 participants (37.3%) with an affective disorder at baseline, a persisting/recurrent disorder was present at follow-up. A modest association existed between SAF and incident affective disorders (OR=1.07 [95%CI 1.03–1.12], P

Introduction Toxoplasma gondii (T. gondii), a parasitic protozoa that is associated with various psychiatric disorders. Both T. gondii infection and disturbed host's lipid profile are common in schizophrenia patients. However, the underlying pathophysiological mechanisms remain speculative. Also, the characteristics of serum lipid levels in schizophrenia patients comorbid with T. gondii infection are not clear. Therefore, it is necessary to explore the influence of chronic T. gondii infection on the characteristic physiological indexes of schizophrenia patients so as to provide some insights into finding target therapeutic drugs. Methods In this study, the effect of chronic T. gondii infection on serum lipid profile was retrospectively analysed in 1719 schizophrenic patients and 1552 healthy subjects from Eastern China. Results The overall prevalence of Immunoglobulin G (IgG) antibodies against T. gondii (17.98%) in schizophrenia patients was significantly higher than healthy controls (7.35%, χ2 = 81.831, P = 0.000). Compared to T. gondii IgG-seronegative schizophrenia patients, IgG-seropositive group had higher high-density lipoprotein (HDL) (P = 0.000) and triglycerides (TG) (P = 0.000) levels, while total cholesterol (TC) (P = 0.000) levels showed an opposite tendency in IgG-seropositive cases. We also found significant correlation between T. gondii seropositivity and increased TG (P = 0.000) and TC levels (P = 0.000) in schizophrenia patients. Binary regression analysis also showed that decreased TC level was more common among schizophrenia patients with T. gondii seropositivity compared to seronegative subjects (OR = 0.617, 95%CI = 0.509–0.749, P = 0.000). Conclusion Patients with chronic T. gondii infection and comorbid schizophrenia had higher HDL and TG levels, while cholesterol levels showed an opposite trend. To the best of our knowledge, this is the first report focus on the host's lipid profile of chronic T. gondii infection and comorbid schizophrenia patients.

The early psychosis movement was fuelled by the concept that early recognition and treatment of patients with psychosis could prevent long-term chronic impairment. Indeed, duration of untreated psychosis (DUP) predicts treatment response and early intervention services have since shown added value. However, considerable chronic impairment remains, with about 20%–30% of the patients with schizophrenia not responding to 2 different conventional antipsychotics in adequate doses and duration. In contrast to the research on DUP and early intervention in schizophrenia in general, far less research has systemically assessed the benefits of shortening the time between treatment onset and adequate treatment response. Yet timely recognition of treatment-resistant schizophrenia (TRS) could be vital since studies have indicated that a critical time window in which clozapine is most effective for TRS patients could exist. We believe that introducing the concept of Duration of Treatment Resistance (DTR) may help to investigate whether shortening of DTR by optimizing medication schedules can further prevent or mitigate long-term disability in patients with schizophrenia. In this editorial, we propose a definition of DTR and encourage the field to investigate the potential merits of this concept in future studies.

Background Patients with psychiatric disorders, such as major depressive disorder, schizophrenia or obsessive-compulsive disorder, often suffer from cognitive dysfunction. The nature of these dysfunctions and their relation with clinical symptoms and biological parameters is not yet clear. Traditionally, cognitive dysfunction is studied in patients with specific psychiatric disorders, disregarding the fact that cognitive deficits are shared across disorders. The Across study aims to investigate cognitive functioning and its relation with psychiatric symptoms and biological parameters transdiagnostically and longitudinally. Methods The study recruits patients diagnosed with a variety of psychiatric disorders and has a longitudinal cohort design with an assessment at baseline and at one-year follow-up. The primary outcome measure is cognitive functioning. The secondary outcome measures include clinical symptoms, electroencephalographic, genetic and blood markers (e.g., fatty acids), and hair cortisol concentration levels. Discussion The Across study provides an opportunity for a transdiagnostic, bottom-up, data-driven approach of investigating cognition in relation to symptoms and biological parameters longitudinally in patients with psychiatric disorders. The study may help to find new clusters of symptoms, biological markers, and cognitive dysfunctions that have better prognostic value than the current diagnostic categories. Furthermore, increased insight into the relationship among cognitive deficits, biological parameters, and psychiatric symptoms can lead to new treatment possibilities. Trial registration Netherlands Trial Register (NTR): NL8170.

Schizophrenia is associated with an increased prevalence of IgG antibodies against Toxoplasma gondii (T. gondii seropositivity), whereby the infection seems to precede the disorder. However, it remains unclear whether a T. gondii infection affects clinical characteristics of schizophrenia. Therefore, a systematic review and meta-analysis was conducted following PRISMA guidelines examining the association between T. gondii seropositivity and severity of total, positive, or negative symptoms or age of onset in schizophrenia. PubMed, Embase, and PsycInfo were systematically searched up to June 23, 2019 (PROSPERO #CRD42018087766). Random-effects models were used for analysis. Furthermore, the influence of potential moderators was analyzed. Indications for publication bias were examined. From a total of 934 reports, 13 studies were included. No overall effect on severity of total, positive, or negative symptoms was found. However, in patients with a shorter duration of illness T. gondii seropositivity was associated with more severe positive symptoms (standardized mean difference [SMD] = 0.32; P < .001). Similar but smaller effects were seen for total symptoms, while it was absent for negative symptoms. Additionally, a significantly higher age of onset was found in those with T. gondii seropositivity (1.8 y, P = .015), although this last finding was probably influenced by publication bias and study quality. Taken together, these findings indicate that T. gondii infection has a modest effect on the severity of positive and total symptoms in schizophrenia among those in the early stages of the disorder. This supports the hypothesis that T. gondii infection is causally related to schizophrenia, although more research remains necessary.

Introduction Patients with schizophrenia have an elevated mortality risk compared to the general population, with cardiovascular-related deaths being the leading cause. The role of clozapine use in the long-term mortality risk is unclear. While clozapine treatment may increase the risk for cardiovascular mortality, it may have protective effects regarding suicidal behavior. Methods We systematically searched EMBASE, MEDLINE, and PsycINFO and reviewed studies that used a long-term follow-up (ie, >52 weeks) and reported on mortality in adults diagnosed with schizophrenia-spectrum disorders who had received clozapine treatment. Results Altogether, 24 studies reported on 1327 deaths from any causes during 217691 patient years in patients treated with clozapine. The unadjusted mortality rate in 22 unique samples during a follow-up of 1.1-12.5 (median = 5.4) years was 6.7 (95% confidence interval [CI] = 5.4-7.9) per 1000 patient years. Long-term, crude mortality rate ratios were not significantly lower in patients ever treated with clozapine during follow-up, but significantly lower in patients continuously treated with clozapine compared to patients with other antipsychotics (mortality rate ratio = 0.56, 95% CI = 0.36-0.85, P-value = .007). Few studies reported on rates of long-term cause-specific mortality (suicide and ischemic heart disease), which showed no significant difference in patients using clozapine compared to patients using other antipsychotics. Statistical heterogeneity was high in all analyses. Discussion Continuous clozapine treatment in schizophrenia patients was associated with a significantly lower long-term all-cause mortality rate compared to other antipsychotic use. These findings, combined with the known efficacy of clozapine, give reason to re-evaluate the hesitancy to prescribe clozapine in regular care settings. Trial registration PROSPERO CRD42017069390.

A systematic review of the current literature on the efficacy of baclofen, particularly the effect of dosing, for the treatment of alcohol dependence (AD) is missing. We therefore conducted a systematic review and meta-analysis of currently available randomized placebo-controlled trials (RCTs). A systematic literature search for RCTs in AD patients comparing baclofen to placebo was performed in September 2017. The effect of baclofen treatment, and the moderating effects of baclofen dosing (low-dose (LDB) 30-60 mg versus high-dose (HDB) targeted as >60 mg/day), and the amount of alcohol consumption before inclusion were studied. Three treatment outcomes were assessed: time to lapse (TTL), percentage days abstinent (PDA), and percentage of patients abstinent at end point (PAE). 13 RCTs from 39 records were included. Baclofen was superior to placebo with significant increases in TTL (8 RCTs, 852 patients; SMD=0.42; 95% CI 0.19-0.64) and PAE (8 RCTs, 1244 patients; OR=1.93; 95% CI 1.17-3.17), and a non-significant increase in PDA (7 RCTs, 457 patients; SMD=0.21; 95% CI -0.24 to 0.66). Overall, studies with LDB showed better efficacy than studies with HDB. Furthermore, tolerability of HDB was low, but serious adverse events were rare. Meta-regression analysis showed that the effects of baclofen were stronger when daily alcohol consumption before inclusion was higher. Baclofen seems to be effective in the treatment of AD, especially among heavy drinkers. HDB is not necessarily more effective than LDB with low tolerability of HDB being an import limitation.

Objective: Profoundly increased mortality rates in schizophrenia, largely caused by a higher risk and earlier onset of cardiovascular disease, remain a major challenge. During the human lifespan, advanced glycation end products (AGEs) accumulate, and their concentration is strongly linked to cardiovascular mortality. AGE accumulation can be accelerated by several pathways, including oxidative stress.Methods: From March 2015 through January 2016, a case-control study including 111 patients with a recent-onset psychosis, 135 controls from a validation cohort, and 286 healthy controls was performed. Patients fulfilled the DSM-IV criteria for schizophrenia spectrum disorders with an illness duration shorter than 5 years. Main outcome parameters were skin autofluorescence levels of AGEs, controlled for age, gender, and smoking. Correlations of AGEs with cardiovascular risk factors and clinical variables were analyzed by hierarchical linear regression analyses.Results: An AGE measurement was possible in 77.4% of cases. AGEs were elevated by 15.1% in recent-onset psychosis compared to healthy controls (P Conclusions: Patients with a recent onset of psychosis have increased AGE levels compared to healthy controls. These findings argue for an earlier implementation of treatment strategies aimed at preventing cardiovascular disease. Also, low-dose strategies of antipsychotics in schizophrenia could beneficially influence AGE levels. (c) Copyright 2017 Physicians Postgraduate Press, Inc.

Exposure to neurotropic pathogens has been hypothesized to be a risk factor for the development of bipolar disorder (BD). However, evidence so far is inconsistent. We, therefore, analyzed the seroprevalence and titer levels of IgG antibodies against several herpesviruses and Toxoplasma gondii (T. gondii) in plasma of 760 patients with a bipolar disorder, 144 first-degree matched relatives and 132 controls of the Dutch Bipolar (DB) Cohort using ELISA. In addition, we performed a literature-based meta-analysis on the seroprevalence of IgG antibodies against these pathogens (n = 14). Our results in the DB Cohort and subsequent meta-analysis (n = 2364 BD patients, n = 5101 controls) show no association between exposure to herpesviruses and bipolar disorder (HSV-1 [adjusted OR 0.842, 95% CI 0.567–1.230], HSV-2 [adjusted OR 0.877, 95% CI 0.437–1.761], CMV [adjusted OR 0.884 95% CI 0.603–1.295], EBV [adjusted OR 0.968 95% CI 0.658–1.423]). In the DB Cohort, we did not find an association between bipolar disorder and T. gondii titer or seroprevalence either [adjusted OR 1.018, 95% CI 0.672–1.542]. The overall OR was not significant for T. gondii [OR: 1.4, 95% CI 0.95–1.90, p = 0.09), but subgroup analyses in age groups below 40 years showed a significantly increased seroprevalence of T. gondii IgGs in BD [OR: 1.8 (95% CI 1.10–2.89, p = 0.021]. Our meta-analysis indicates that T. gondii exposure may be a risk factor for BD in certain subpopulations.

Background: Schizophrenia is associated with an increased risk of sudden cardiac death, traditionally attributed to prolongedQTc interval and increasedprevalence of cardiovascular risk factors. However, defective ion channels implicated in both schizophrenia and Brugada Syndrome (BrS)may be associated with an increased risk of cardiac arrhythmias. Moreover, these cardiac arrhythmias can be provoked by various drugs, including psychotropic drugs. Objective: To assess the prevalence of the occurrence of ECG suspicious for BrS (suspect BrS-ECG) and the prevalence of BrS in patients with recent onset schizophrenia spectrum disorders (SSD). Methods: In this case-control study, ECGs of 388 patients with recent onset SSD admitted between 2006 and 2015 and 844 healthy controls weremade. All persons who had a suspect BrS-ECG were offered an ajmaline provocation test to diagnose or exclude BrS. Data on possible confounders were ascertained. Patients with and without suspect BrS-ECG were compared regarding clinical and ECG variables. Results: Suspect BrS-ECG was found in 33 patients (8.5%) and 13 healthy controls (1.5%),with an adjustedOdds Ratio of 3.5 (p b 0.0001). This findingwas not explained by potential confounders such as gender, age, ethnicity, cannabis use, cardiovascular risk factors, medication use or serum electrolytes. BrSwas confirmed in three patients and one control. Conclusion: A considerable subset of patientswith recent onset SSD have suspect BrS-ECG, extending earlier findings in patients with chronic schizophrenia. Screening for BrS in schizophrenia could be relevant both to prevent sudden cardiac death and to identify a subgroup of patients with possible ion-channel dysfunctioning.

Unnatural causes of death due to traffic accidents (TA) and suicide attempts (SA) constitute a major burden on global health, which remained stable in the last decade despite widespread efforts of prevention. Recently, latent infection with Toxoplasma gondii (T. gondii) has been suggested to be a biological risk factor for both TA and SA. Therefore, a systematic search concerning the relationship of T. gondii infection with TA and/or SA according to PRISMA guidelines in Medline, Pubmed and PsychInfo was conducted collecting papers up to 11 February 2019 (PROSPERO #CRD42018090206). The random-effect model was applied and sensitivity analyses were subsequently performed. Lastly, the population attributable fraction (PAF) was calculated. We found a significant association for antibodies against T. gondii with TA [odds ratio (OR) = 1.69; 95% confidence interval (CI) 1.20–2.38, p = 0.003] and SA (OR = 1.39; 95% CI 1.10–1.76, p = 0006). Indication of publication bias was found for TA, but statistical adjustment for this bias did not change the OR. Heterogeneity between studies on SA was partly explained by type of control population used (ORhealthy controls = 1.9, p < 0.001 v. ORpsychiatric controls = 1.06, p = 0.87) and whether subjects with schizophrenia only were analysed (ORschizophrenia = 0.87, p = 0.62 v. ORvarious = 1.8, p < 0.001). The association was significantly stronger with higher antibody titres in TA and in studies that did not focus on schizophrenia subjects concerning SA. PAF of a T. gondii infection was 17% for TA and 10% for SA. This indicates that preventing T. gondii infection may play a role in the prevention of TA or SA, although uncertainty remains whether infection and outcome are truly causally related.

BACKGROUND: Traditionally, schizophrenia and major depressive disorder (MDD) are seen as separate disorders based on their distinct clinical presentation. In clinical practice however, overlapping symptoms are noticeable such as psychotic symptoms, apathy and cognitive decline. Schizophrenia and MDD are both associated with increased risks of immune disorders and metabolic syndrome. However, it is unclear whether dysfunctions in growth factors, the immune and metabolic system underlie the psychopathology of both schizophrenia and MDD without the influence of chronic illness and treatment. In this meta-analysis we aimed to answer the following question: which peripheral growth, immune and glucose metabolism proteins are similarly altered in drug-naïve first-episode patients with either schizophrenia or MDD compared with healthy controls? METHODS: We conducted a meta-analysis of studies providing serum or plasma measurements (in mean and standard deviation) of peripheral protein markers regarding growth, immune and glucose metabolism proteins in drug-naïve first-episode patients with schizophrenia or MDD and healthy controls. We used a random-effects meta-analysis for which mean differences were quantified with Hedges’ g (g). RESULTS: A total of 65 case-control studies were retrieved comprising of 3156 drug-naïve and first-episode schizophrenia patients and 3687 controls, and a total of 29 studies were retrieved comprising of 1077 drug-naïve and first-episode MDD patients and 1405 controls. In schizophrenia patients brain-derived neurotrophic factor (BDNF) (g = -0.80, 95% CI -1.00 to -0.61; P < 0.01) and nerve growth factor (NGF) (g = -3.28, 95% CI -6.35 to -0.21; P = 0.04) were significantly decreased, and interleukin 6 (IL-6) (g = 1.03, 95% CI 0.61 to 1.46; P < 0.01), interleukin 8 (IL-8) (g = 0.65, 95% CI 0.11 to 1.18; P = 0.02), tumor necrosis factor alpha (TNFα) (g = 0.51, 95% CI 0.19 to 0.83; P < 0.01), fasting glucose concentration (g = 0.26, 95% CI 0.08 to 0.44; P < 0.01) and fasting insulin concentration (g = 0.40, 95% CI 0.13 to 0.68; P < 0.01) were all significantly elevated compared with controls. In MDD patients C-reactive protein (CRP) (g = 0.45, 95% CI 0.18 to 0.71; P < 0.01), interleukin 1 beta (IL-1β) (g = 1.52, 95% CI 0.38 to 2.66; P < 0.01), interleukin 2 (IL-2) (g = 4.41, 95% CI 0.13 to 8.69; P = 0.04), IL-6 (g = 0.62, 95% CI 0.17 to 1.06; P < 0.01) and TNFα (g = 1.21, 95% CI 0.57 to 1.85; P < 0.01) were all significantly elevated compared with controls. IL-8 was significantly decreased in MDD patients compared with controls (g = -0.84, 95% CI -1.48 to -0.20; P < 0.01). CRP, IFNγ, IL-1β, IL-2, IL-4, interleukin 10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) were not significantly altered in schizophrenia patients compared with controls. However, for IL-4 we observed a trend of increased levels in schizophrenia. BDNF, NGF, IFNγ, IL-10, fasting insulin concentration and MCP-1 were not significantly altered in MDD patients compared with controls. However, a similar trend of increased levels of CRP was seen for schizophrenia when compared to MDD, and decreased levels of BDNF and NGF and elevated levels of fasting glucose concentration were seen for MDD when compared to schizophrenia. DISCUSSION: This meta-analysis suggests that dysfunctions in growth, immune and glucose metabolism markers are already present in patients with schizophrenia and MDD from disease onset without the influence of psychotropic treatment. Strikingly, of the 14 proteins identified in this meta-analysis, 10 (71%) are changed in the same direction (trends included) or unchanged in both schizophrenia and MDD. Our findings indicate shared preventive strategies and on-time treatment for immune and metabolic dysfunctions prevalent in these disorders.

Treatment resistance (TR) in psychosis is a major clinical problem. A biomarker predicting TR against conventional antipsychotic drugs would be relevant, potentially reducing unnecessary delay to adequate treatment with clozapine. Dopa decarboxylase (DDC) activity in the striatum, measured with positron emission tomography, is elevated in responders, but not in treatment-resistant patients. Plasma DDC activity could be a surrogate marker for DDC brain activity, and thus a potential biomarker that could be used in daily clinical practice. Therefore, we determined plasma DDC activity in 40 male patients with recent-onset psychosis, of whom the majority had started treatment, whereby 21 turned out to be treatment responders and 19 treatment resistant during follow up. We observed no significant group differences. Furthermore, symptom severity was not associated with plasma DCC activity. We did observe a trend level difference in the distribution of plasma DDC activity across categories of medication, with subsequent post hoc analysis showing lower DDC activity in risperidone-using patients. This may suggest that risperidone could influence plasma DDC activity. Based on these results, plasma DDC activity does not appear to be a promising biomarker for TR in recent-onset psychosis patients who are already receiving antipsychotic treatment.

BackgroundDespite evidence for the effects of metals on neurodevelopment, the long-term effects on mental health remain unclear due to methodological limitations. Our objective was to determine the feasibility of studying metal exposure during critical neurodevelopmental periods and to explore the association between early-life metal exposure and adult schizophrenia.MethodsWe analyzed childhood-shed teeth from nine individuals with schizophrenia and five healthy controls. We investigated the association between exposure to lead (Pb2+), manganese (Mn2+), cadmium (Cd2+), copper (Cu2+), magnesium (Mg2+), and zinc (Zn2+), and schizophrenia, psychotic experiences, and intelligence quotient (IQ). We reconstructed the dose and timing of early-life metal exposures using laser ablation inductively coupled plasma mass spectrometry.ResultsWe found higher early-life Pb2+ exposure among patients with schizophrenia than controls. The differences in log Mn2+ and log Cu2+ changed relatively linearly over time to postnatal negative values. There was a positive correlation between early-life Pb2+ levels and psychotic experiences in adulthood. Moreover, we found a negative correlation between Pb2+ levels and adult IQ.ConclusionsIn our proof-of-concept study, using tooth-matrix biomarker that provides direct measurement of exposure in the fetus and newborn, we provide support for the role of metal exposure during critical neurodevelopmental periods in psychosis.

Schizophrenia is associated with excessive oxidative stress. Production of advanced glycation end products (AGEs) in the skin is strongly associated with oxidative stress. Increased skin AGE-levels have been demonstrated at cross-sectional level in recent onset psychosis and chronic schizophrenia, indicating increased cardiovascular risk. We aimed to investigate factors underlying AGE-accumulation and accumulation rate of AGEs in recent onset psychosis. From December 2016 through May 2017, 66 patients and 160 (highly educated) healthy controls from a previous case-control study of AGE-levels were assessed for a follow-up measurement 12-24 months after baseline. Possible determinants of AGE-accumulation were analyzed. AGE-accumulation rates in patients and controls were compared adjusted for relevant confounders. In healthy controls, a significant association of AGE-accumulation with ethnicity and tobacco exposure was found. An indication of a markedly higher AGE-accumulation rate was found in patients suffering from recent onset psychosis compared to healthy controls, independent of ethnicity and tobacco smoking, but not independent of cannabis use (more prevalent in patients than controls), although results were not significant.

Objective To estimate the incidence rates (IRs) of bipolar I and bipolar II disorders in the general population according to sociodemographic population characteristics. Methods A cohort study (during the years 1996–2007) was conducted in a general practitioners research database with a longitudinal electronic record of 800000 patients throughout the Netherlands [the Integrated Primary Care Information (IPCI) database]. Cases of bipolar disorder were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, degree of urbanization, and degree of deprivation. Results The overall IR of bipolar disorder was 0.70/10000 person-years (PY) [95% confidence interval (CI): 0.57–0.83]; the IR of bipolar I disorder was 0.43/10000 PY (95% CI: 0.34–0.55) and the IR of bipolar II disorder was 0.19/10000 PY (95% CI: 0.13–0.27). Two peaks in the age at onset of the disorder were noticed: one in early adulthood (15–24 years; 0.68/10000 PY) and a larger peak in later life (45–54 years; 1.2/10000 PY). In bipolar II disorder, only one peak, in the 45–54 year age category (IR 0.42/10000 PY), was found. The IRs of bipolar disorder were significantly higher in deprived areas. Similar rates were found for men compared to women and in urban compared to rural areas. No association was found between the onset of first (hypo)manic episode and month or season of birth. Conclusions We found two peaks in the age at onset of bipolar disorder, one in early adulthood and one in later life, the former consisting mainly of bipolar I disorder subjects. The incidence of bipolar disorder is higher in deprived areas. The onset of bipolar disorder is not associated with gender, urbanization, or month or season of birth.

Evidence is accumulating that immune dysfunction is involved in the pathophysiology of schizophrenia. It has been hypothesized that microglia activation is present in patients with schizophrenia. Various in vivo and post-mortem studies have investigated this hypothesis, but as yet with inconclusive results. Microglia activation is associated with elevations in 18 kDa translocator protein (TSPO) levels, which can be measured with the positron emission tomography (PET) tracer (R)-[11C]PK11195. The purpose of the present study was to investigate microglia activation in psychosis in vivo at an early stage of the disease. (R)-[11C]PK11195 binding potential (BPND) was measured in 19 patients with recent onset psychosis and 17 age and gender-matched healthy controls. Total gray matter, as well as five gray matter regions of interest (frontal cortex, temporal cortex, parietal cortex, striatum, and thalamus) were defined a priori. PET data were analysed using a reference tissue approach and a supervised cluster analysis algorithm to identify the reference region. No significant difference in (R)-[11C]PK11195 BPND between patients and controls was found in total gray matter, nor one of the regions of interest. These findings suggest that microglia activation is not present in recent onset psychosis or that it is a subtle phenomenon that could not be detected using the design of the present study.

Background Patients with schizophrenia have a high mortality risk. The role of clozapine in the long-term mortality risk is insufficiently known. The objectives of the current study were to determine in i) all-cause long-term mortality rates and ii) specific-cause mortality rates and ratios in patients with schizophrenia with and without clozapine treatment. Methods We systematically searched EMBASE, MEDLINE and PsycINFO and included studies that used a long-term follow-up design (i.e., ≥52 weeks) and reported on mortality in adults diagnosed with schizophrenia-spectrum disorders receiving clozapine treatment. Results Altogether, 23 studies fulfilled our criteria, reporting on 1,166 deaths during 203,231 patient years for patients treated with clozapine. Pooling five cohort studies that included sufficient sample sizes and length of follow-up, we found an unadjusted mortality rate of 7.34 per 1,000 patient years (95%CI=4.39–10.28). Long-term, crude mortality rate ratios were significantly lower in patients treated with clozapine compared to patients without clozapine treatment (mortality rate ratio=0.59, 95%CI=0.43–0.81, p-value

Delusional infestation, formally known as delusional parasitosis, poses a therapeutic challenge. This article provides tools to engage these patients with psychiatric treatment. We present two men aged 49 and 48 who saw the dermatologist with skin symptoms due to primary and secondary delusional infestation, respectively. Despite their anosognosia, both patients were successfully treated with antipsychotics thanks to the collaboration between dermatology and psychiatry. To increase the acceptability of treatment with antipsychotics, emphasis should be placed on their antipruritic properties and the effect on degree of preoccupation with the infection rather than their antipsychotic properties. Follow-up is important, as patients mostly do not attribute their recovery to antipsychotics and the risk of recurrence is high after cessation of antipsychotic medication.

Longitudinal incidence studies of schizophrenia spectrum disorders (SSD) performed in mental health service organizations are prone to confounding factors not found in research performed in the general population. To estimate the incidence rates (IRs) over a 10-year period of SSD (broadly defined) and schizophrenia (narrowly defined) in the general population and to analyze associated risk factors. A cohort study (1996-2006) in a large general practitioners research database was conducted with longitudinal medical records of 350,524 patients throughout the Netherlands. Cases of SSD were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, date of birth, degree of urbanicity and deprivation. Overall IR of SSD in this population was 22/100,000 person years (PY) (95% CI 19-24). IR of schizophrenia was 12/100,000 PY (95% CI 10-14). Period prevalence was 3.5 per 1,000 PY. IRs were higher in men compared to women, had a peak at age 15-25 years, decreasing rapidly after 25 years by 40% per 10 years. IRs of SSD were significantly higher in urban areas, irrespective of deprivation. No association was found between IRs of SSD and living in deprived areas or month of birth. There was no significant time trend of the IR during the period under study. IRs of SSD are higher in urban areas, independent of social deprivation. Age- and gender-specific differences in IR were found. The magnitude of these differences was larger in narrowly defined schizophrenia than in SSD

The patient in this case report had two severe medical conditions that require oppositional treatment: prolactinoma and psychosis. A prolactinoma is a benign tumour of the pituitary gland that produces prolactin. Dopamine agonist medication is the first-line treatment in patients with prolactinoma. The psychotic symptoms started after a dosage increase of a dopamine D2-receptor agonist. Several antipsychotic medications were tried with and without the dopamine D2-receptor agonist, but severe command hallucinations remained. Cognitive behavioural therapy (CBT) was added which reduced the impact of the hallucinations to a great extent, indicating that CBT can have an additional positive effect in prolactinoma patients with psychosis that shows incomplete recovery after antipsychotic medication. Future research should be aimed at the severe and prolonged side effects of dopamine agonists in the treatment of prolactinoma patients with multiple risk factors for a psychotic decompensation. Copyright 2011 BMJ Publishing Group. All rights reserved.

Introduction An association between Toxoplasma gondii (T. gondii) and schizophrenia has been shown by a meta-analysis showing a significant Odds Ratio (OR) of 2.7. Currently, several studies have looked at the association between T. gondii and other psychiatric disorders as well, rendering exploration of diagnostic specificity possible. Furthermore, questions remain on the timing and nature of the infection. Methods A systematic search was performed to identify relevant studies of all major psychiatric disorders versus healthy controls in relation to T. gondii infection. Methodological quality, heterogeneity and risk of bias were assessed. Results A total of 2866 studies were found, from which 51 studies were finally included. Significant ORs were found for Schizophrenia, Bipolar Disorder, OCD and Addiction, but not for Major Depression. Further exploration of the association between T. gondii and schizophrenia, yielded a significant association of seropositivity before onset of psychosis and with high antibody titers. A decline of the association was found when baseline exposure in the healthy control population increased. Discussion These findings suggest that T. gondii infection is not merely associated with psychosis and that in schizophrenia a reactivation of a latent T. gondii infection occurs. Several hypotheses remain open about the nature of this association.

Introduction Schizophrenia is associated with an increased risk of sudden cardiac death, traditionally attributed to prolonged QTc interval and cardiovascular risk factors such as metabolic syndrome. However, defective ion channels are also implicated in schizophrenia. This applies as well for Brugada syndrome (BrS), a rare hereditary cardiac disorder associated with an increased risk of cardiac arrhythmias, which can been provoked by various drugs, including psychotropic. Objectives To screen whether an increased prevalence of suspect Brugada ECG is present in patients with recent onset schizophrenia. Methods 273 subjects with recent onset schizophrenia admitted between 2006 and 2012 and 306 healthy controls, underwent an ECG. All persons who had an ECG suspect for BrS were asked to undergo a provocation test to diagnose/exclude BrS. We checked whether patients had deceased during follow-up. Results 20/273 patients (7.3%) and 5/306 healthy controls (1.6%) showed an ECG suspect for BrS, with a Relative risk (RR) of 4.8 (p Conclusion: This study shows that a considerable subset of patients with recent onset schizophrenia have an ECG suspect of Brugada Syndrome, confirming results in a population with chronic schizophrenia (Blom 2014). This may imply that there is a common pathophysiologic mechanism involved in both disorders. Screening for Brugada Syndrome in schizophrenia is relevant to prevent sudden cardiac death.