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BackgroundCognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes.Methods204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up.ResultsThree distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present.ConclusionsCurrent results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.

Contains fulltext : 244699.pdf (Publisher’s version ) (Open Access) Schizophrenia-spectrum disorders (SSD) are associated with increased inflammatory markers, both in brain and periphery. Augmentation with drugs that lower this pro-inflammatory status may improve clinical presentation. Simvastatin crosses the blood-brain barrier, has anti- inflammatory and neuroprotective effects and reduces metabolic syndrome. In this study, we investigated if 12 months of simvastatin augmentation can improve symptoms and cognition in patients with early SSD. This double-blind placebo-controlled trial included 127 SSD patients across the Netherlands

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.

The etiology of psychotic disorders is still unknown, but in a subgroup of patients symptoms might be caused by an autoimmune reaction. In this study, we tested patterns of autoimmune reactivity against potentially novel hippocampal antigens. Serum of a cohort of 621 individuals with psychotic disorders and 257 controls were first tested for reactivity on neuropil of rat brain sections. Brain reactive sera (67 diseased, 27 healthy) were further tested for antibody binding to glutamic acid decarboxylase (GAD) isotype 65 and 67 by cell-based assay (CBA). A sub-cohort of 199 individuals with psychotic disorders and 152 controls was tested for the prevalence of anti-nuclear antibodies (ANA) on HEp2-substrate as well as for reactivity to double-stranded DNA, ribosomal P (RPP), and cardiolipin (CL). Incubation of rat brain with serum resulted in unidentified hippocampal binding patterns in both diseased and control groups. Upon screening with GAD CBA, one of these patterns was identified as GAD65 in one individual with schizophrenia and also in one healthy individual. Two diseased and two healthy individuals had low antibody levels targeting GAD67 by CBA. Antibody reactivity on HEp-2-substrate was increased in patients with schizoaffective disorder, but only in 3 patients did antibody testing hint at a possible diagnosis of systemic lupus erythematosus. Although reactivity of serum to intracellular antigens might be increased in patients with psychotic disorder, no specific targets could be identified. GAD antibodies are very rare and do not seem increased in serum of patients with psychotic disorders. ispartof: Schizophrenia Research vol:228 pages:462-471 ispartof: location:Netherlands status: Published online

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.

The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signalling and is predominant in leukocytes. Gain-of-function (GOF) mutations in the PIK3CD gene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role of PIK3CD in cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of the PIK3CD GOF mutation in neurological deficits using a murine model of this disease. We used E1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δE1020K mice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate that PIK3CD GOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments.

Research has found that Obsessive Compulsive Symptoms (OCS) in schizophrenia are associated with either more or less negative symptoms and either better or poorer cognitive functioning. In order to explain these contradictory results, (Lysaker et al., 2004), performed a cluster analysis resulting in 2 OCS positive (OCSpos) clusters, one with higher functioning (HF) and one with poorer functioning (PF) compared to 2 OCS negative (OCSneg) clusters. The OCSpos/HF cluster had less negative symptoms compared to all other clusters, while the OCSpos/PF cluster showed poorer executive functioning. We performed a replication study, in an almost 10 times larger, representative sample, using both a longitudinal and cross-sectional design. Similar to Lysaker et al., we found a group with mild OCS and HF (OCSmild/HF) showing less negative symptoms compared to the PF groups. We also found an OCSmild/PF group, which did not significantly differ in executive functioning from the other groups. Moreover, we did not find evidence for a better prognosis in the OCSmild/HF group, and thus found no support for the assumption that for some patients OCS might be an effective coping mechanism. ispartof: PSYCHIATRY RESEARCH vol:271 pages:421-427 ispartof: location:Ireland status: published

Evidence shows that a propensity toward a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs). For this literature update, PubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes. Our search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and Withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06–0.54], estrogens (ES: 0.78; n = 723; CI 0.36–1.19), minocycline (ES: 0.40; n = 946; CI 0.11–0.68), and NAC (ES: 1.00; n = 442; CI 0.60–1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect. In conclusion we found that some, but not all, agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.

Many individuals with severe mental disorders have difficulties in vocational and social functioning, which are regarded the most important outcomes, together with clinical symptoms. To understand the underlying mechanisms, research is increasingly focused on factors influencing functional outcomes. One established association has been shown between cognition and community functioning with negative symptoms as a possible mediator. Although it has been shown that negative symptoms consist of two subdomains, thus far negative symptoms have been assessed as one unitary construct. This study considers for the first time subdomains of negative symptoms as putative mediators (expressive deficits, amotivation) of the association between cognition (neuro- and social cognition) and functional outcome (living situation, occupation, social functioning). We expected that specific subdomains of negative symptoms (e.g. amotivation) would mediate the effect of cognition on specific functional outcomes (e.g. social functioning) independently from illness duration. To assess this, we included two independent cohorts, consisting of participants with different illness duration. These two independent cohorts consisted of patients with a recent-onset psychotic disorder: PROGR-S (first time treated; N = 1129) and GROUP (illness duration preferably

Background The symptom severity of a substantial group of schizophrenia patients (30–40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood–brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia. Methods/design In total, 90 subjects aged 18–70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted. Discussion It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo. Trial registration ClinicalTrials.gov, NCT02949232 and NCT03340909. Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014–000520-14 and 2017–000163-32.

BackgroundThe prevalence of psychotic experiences (PEs) is higher in low-and-middle-income-countries (LAMIC) than in high-income countries (HIC). Here, we examine whether this effect is explicable by measurement bias.MethodsA community sample from 13 countries (N = 7141) was used to examine the measurement invariance (MI) of a frequently used self-report measure of PEs, the Community Assessment of Psychic Experiences (CAPE), in LAMIC (n = 2472) and HIC (n = 4669). The CAPE measures positive (e.g. hallucinations), negative (e.g. avolition) and depressive symptoms. MI analyses were conducted with multiple-group confirmatory factor analyses.ResultsMI analyses showed similarities in the structure and understanding of the CAPE factors between LAMIC and HIC. Partial scalar invariance was found, allowing for latent score comparisons. Residual invariance was not found, indicating that sum score comparisons are biased. A comparison of latent scores before and after MI adjustment showed both overestimation (e.g. avolition, d = 0.03 into d = −0.42) and underestimation (e.g. magical thinking, d = −0.03 into d = 0.33) of PE in LAMIC relative to HIC. After adjusting the CAPE for MI, participants from LAMIC reported significantly higher levels on most CAPE factors but a significantly lower level of avolition.ConclusionPrevious studies using sum scores to compare differences across countries are likely to be biased. The direction of the bias involves both over- and underestimation of PEs in LAMIC compared to HIC. Nevertheless, the study confirms the basic finding that PEs are more frequent in LAMIC than in HIC.

Cognitive impairments in patients with psychotic disorder have been associated with poor functioning and increased symptom severity. Furthermore, childhood trauma (CT) exposure has been associated with worse cognitive functioning as well as co-occurrence of affective-anxious-psychosis symptoms or a 'mixed phenotype of psychopathology' (MP), which in turn is associated with greater symptom severity, and poor functioning. This study aims to evaluate if cognition could be associated with CT/MP.& para;& para;532 patients with non-affective psychotic patients were assessed on Cl', symptom profile, cognition, functioning, and symptom severity at baseline and 3 and 6-year follow-up. Four subgroups were made according to trauma exposure (CT- or CT+) and presence of a mixed phenotype (MP- or MP +-): CT-/MP (n = 272), CT-I MP+ (n = 157), CT-IMP- (n = 49), and CT+/MP + (n = 54). Mixed-effects multilevel regression, linear regression, and Tobit analyses were performed.& para;& para;Patients with both CT and MP showed lower verbal learning and memory than CT-/MP+ individuals (p

Background: The symptom severity of a substantial group of schizophrenia patients (30-40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients.. Corticosteroids are effective in various chronic inflammatory and auto-immune disorders. From the group of glucocorticosteroids, prednisolone has minor mineral-corticosteroid potencies, can adequately pass the blood-brain barrier (BBB) and its side-effects and safety profile are well known. Therefore, a study into treatment with prednisolone can provide as a proof of concept for immune modulation as a treatment for schizophrenia. Method: In total 90 subjects, aged 18-70 years, diagnosed with schizophrenia, schizoaffective or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.*) or psychosis NOS (not otherwise specified) (298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed seven years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks. Study medication will be initiated at 40 mg for three days, after which it will be tapered down within 6 weeks after initiation, following current treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia; BACS) and change in Global Assessment Functioning (GAF) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, GAF scores and immunological biomarkers. Additionally, a subgroup of patients can participate in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy, structural, functional and diffusion MRI will be conducted. Discussion: It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo. Trial registration: ClinicalTrails.gov NCT02949232 registered at 31 October 2016, retrospectively registered https://clinicaltrials.gov/ct2/show/NCT02949232?term=corticosteroid&cond=schizophrenia&rank=3 ; EudraCT-number 2014-000520-14 and 2017-000163-32.

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.

In the present study, to improve the predictive performance of a model and its reproducibility when applied to an independent data set, we investigated the use of multimodel inference to predict the probability of having a complex psychiatric disorder. We formed training and test sets using proteomic data (147 peptides from 77 proteins) from two-independent collections of first-onset drug-naive schizophrenia patients and controls. A set of prediction models was produced by applying lasso regression with repeated tenfold cross-validation to the training set. We used feature extraction and model averaging across the set of models to form two prediction models. The resulting models clearly demonstrated the utility of a multimodel based approach to make good (training set AUC > 0.80) and reproducible predictions (test set AUC > 0.80) for the probability of having schizophrenia. Moreover, we identified four proteins (five peptides) whose effect on the probability of having schizophrenia was modified by sex, one of which was a novel potential biomarker of schizophrenia, foetal haemoglobin. The evidence of effect modification suggests that future schizophrenia studies should be conducted in males and females separately. Future biomarker studies should consider adopting a multimodel approach and going beyond the main effects of features.

High-content functional screening of primary patient blood cells reveals repurposed psychiatric drug candidates., There is a paucity of efficacious new compounds to treat neuropsychiatric disorders. We present a novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo. Primary T lymphocytes showed functional responses encompassing neuropsychiatric medications and central nervous system ligands at established (e.g., GSK-3β) and emerging (e.g., CrkL) drug targets. Clinical application of the platform to schizophrenia patients over the course of antipsychotic treatment revealed therapeutic targets within the phospholipase Cγ1–calcium signaling pathway. Compound library screening against the target phenotype identified subsets of L-type calcium channel blockers and corticosteroids as novel therapeutically relevant drug classes with corresponding activity in neuronal cells. The screening results were validated by predicting in vivo efficacy in an independent schizophrenia cohort. The approach has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for neuropsychiatric conditions.

If schizotypy is a taxonic liability for schizophrenia with a general population prevalence of ~10%, it should also be taxonic among biological siblings of probands with schizophrenia. Moreover, assuming this is so, siblings' schizotypy class membership should be predicted by probands' familial load for psychotic disorder and clinical severity, consistent with a multifactorial polygenic threshold model of schizophrenia. We tested these hypotheses in the Genetic Risk and Outcome of Psychosis (GROUP) Study where siblings of probands (n = 792) and unaffected controls (n = 559) provided self-report ratings on the Community Assessment of Psychic Experiences (CAPE). Maximum covariance analyses of control group ratings led to the identification of CAPE items sensitive to nonredundant positive and negative schizotypy classes in the control group (prevalence = 7.9% and 11.1%, respectively). When the same taxonic solution was applied to siblings' CAPE rating, taxometric analyses yielded evidence for larger positive and negative schizotypy classes among siblings (prevalence = 14.1% and 21.8%, respectively). Whereas probands' familial loads for bipolar disorder or drug use disorders did not predict siblings' membership in the schizotypy classes, probands' familial load for psychotic disorder did. Siblings were more likely to be members of the positive schizotypy class where their probands were more severely affected. The pattern of findings is consistent with Meehl's argument that schizotypy reflects liability for schizophrenia. ispartof: Schizophrenia Bulletin vol:44 issue:4 pages:922-932 ispartof: location:United States status: accepted

BACKGROUND: The concept of a psychosis continuum implies that the same symptoms seen in patients with psychotic disorders can be measured in a healthy population. The assumption is that experiencing symptoms of psychosis such as delusions and hallucinations is not inevitably associated with the presence of the disorder. Surveys of unselected general population samples have consistently shown that a large number of individuals report experiences that strongly resemble the symptoms seen in psychotic patients. Only a fraction of these individuals met criteria for a clinical disorder such as schizophrenia. Alterations in the metabolic system in antipsychotic-naïve first-episode schizophrenia have been described, posing the question whether these metabolic markers are altered in persons with subclinical psychotic experiences as well. METHODS: We used cross-sectional data of 1890 participants of a prospective population-based cohort study, ‘the Rotterdam Study (ERGO)’. The ages ranged from 45 to 54 years and the participants filled in a self-report questionnaire, ‘The Community Assessment of Psychic Experience’. To assess subclinical psychotic symptoms, the frequency and distress ratings of the positive symptom dimension from this questionnaire were used. These items were offset against metabolic measured parameters. The metabolic parameters used were body-mass index (BMI; body weight in kg/m2), fasting glucose levels, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides and cholesterol. Linear regression analyses were used with adjustment for age, gender, ethnicity, education level, employment status and marital status. The influences of psychopharmacology use, anxiety disorder, depressive symptoms and use of lipid reducing agents on the subclinical psychotic symptoms were analysed in sensitivity analyses. RESULTS: We observed a strong positive association between BMI and the frequency of subpsychotic symptoms, and also with the perceived distress of these subpsychotic symptoms. In participants with a BMI ≥ 30 we observed an even stronger association with the frequency score and distress rating of subpsychotic symptoms. In a restricted sample to non-lipid reducing agent users only, we observed that LDL is negatively associated with the frequency of subpsychotic symptoms and perceived distress of these subpsychotic symptoms. For HDL, we observed a negative association with only the frequency of subpsychotic symptoms. The other metabolic markers, total cholesterol, triglycerides and fasting glucose, did not show any significant associations with subpsychotic symptoms. The use of psychopharmaceuticals, the presence of an anxiety disorder or experiencing depressive symptoms did not alter our results. DISCUSSION: In this study of a large community sample we found that increased BMI and metabolic dysfunctions are associated with subclinical psychotic experiences. Our findings add to the evidence that psychotic phenomena are related to alterations in the metabolism and obesity even without antipsychotic medication use. Noticeably, this association seems also to hold for subclinical psychotic phenomena, present in the normal population.

Viral infections during the prenatal or early childhood periods are one of the environmental factors which might play an etiological role in psychoses. Several studies report higher antibody levels against viruses during pregnancy in blood of mothers of offspring with psychotic disorders, but the presence of such viruses has never been demonstrated. The goal of this study was to investigate the potential association between viral infections during pregnancy and progeny with psychotic disorders and, for this purpose, we performed a nested case control study involving pregnant mothers of offspring with schizophrenia or bipolar disorder with psychotic features (cases, N = 43) and pregnant women with healthy offspring (controls, N = 95). Since several potential viral candidates have been suggested in prior work, a broad-spectrum virus detection system was necessary. A metagenomic analysis performed with the virus discovery method VIDISCA-454 revealed only common blood-associated viruses in all cohorts. However, a significantly lower viral prevalence was detected in the group of cases and in the sub-population of pregnant mothers of offspring with schizophrenia (p < 0.05). Consistent with the existing inverse correlation between the level of these viruses and the immunocompetence of an individual, we hypothesized the presence of a higher immune activity during pregnancy in mothers whose offspring later develop a psychotic disorder as compared to controls. Combining our results with previously available literature data on antibody levels during the gestation period suggests that a more prominent maternal immune activity can be considered a risk factor for developing psychosis. (C) 2015 Elsevier B.V. All rights reserved.

The objective of this study was to evaluate the psychometric properties of the 20-item version of the Subjective Well-being Under Neuroleptic Treatment Scale (SWN) in patients, their siblings and parents and in healthy controls. In order to study heritability of subjective well-being, assessment in unaffected relatives and healthy controls is necessary. Data were obtained from the Dutch GROUP study (Genetic Risk and Outcome of Psychosis), a large cohort study on non-affective psychotic disorders incorporating patients, their relatives and healthy controls. The SWN scale and other relevant assessments were completed by 545 schizophrenia patients, 541 siblings, 75 parents, and 280 healthy controls. Reliability within the four groups ranged between Cronbach's alpha 0.88 and 0.92. Factor analysis indicated a single factor structure of the SWN scale, which makes only SWN total scores relevant. The WHO-Quality of Life psychological domain correlated highly with SWN total scores in all groups. Subclinical psychotic experiences were found to be associated with SWN total scores in relatives and healthy controls, supporting the psychosis continuum concept. The 20-item SWN scale is a reliable measure for subjective well-being that can also be used in relatives and healthy controls to investigate genetic and psychological dispositions of subjective well-being. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Cannabis use has been associated with favorable outcomes on metabolic risk factors. The cause of this relation is still unknown. In this study we investigated whether this effect is mediated by the AKT1 gene, as activation of the related enzyme by cannabis may cause metabolic changes.Six Single Nucleotide Polymorphisms (SNPs) of the AKT1 gene (rs1130214, rs1130233, rs2494732, rs2498784, rs3730358, and rs3803300) of patients with psychotic disorders (n = 623) were related to Body Mass Index (BMI), levels of glycosylated hemoglobin (HBA(1c)) and total metabolic risk. Next, mediation analysis was performed with BMI as outcome, cannabis as predictor, and AKT1 as mediator. Cannabis use was inversely related to BMI but not with levels of HBA(1c) and totalmetabolic risk. Moreover, out of 6 AKT1 SNPs, rs2494732 was associated with cannabis use, but AKT1 did not mediate the effect of cannabis on BMI.In conclusion, cannabis use is likely to be associated with a lower BMI in patients with a psychotic disorder. Moreover, AKT1 risk alleles may increase the incidence of cannabis use in patients with a psychotic disorder, but AKT1 does not appear to mediate the effect of cannabis on BMI. (C) 2016 Elsevier B.V. All rights reserved.

BACKGROUND: Bipolar disorder (BD) is a costly, devastating and life shortening mental disorder that is often misdiagnosed, especially on initial presentation. Misdiagnosis frequently results in ineffective treatment. We investigated the utility of a biomarker panel as a diagnostic test for BD. METHODS AND FINDINGS: We performed a meta-analysis of eight case-control studies to define a diagnostic biomarker panel for BD. After validating the panel on established BD patients, we applied it to undiagnosed BD patients. We analysed 249 BD, 122 pre-diagnostic BD, 75 pre-diagnostic schizophrenia and 90 first onset major depression disorder (MDD) patients and 371 controls. The biomarker panel was identified using ten-fold cross-validation with lasso regression applied to the 87 analytes available across the meta-analysis studies. We identified 20 protein analytes with excellent predictive performance [area under the curve (AUC)?0.90]. Importantly, the panel had a good predictive performance (AUC 0.84) to differentiate 12 misdiagnosed BD patients from 90 first onset MDD patients, and a fair to good predictive performance (AUC 0.79) to differentiate between 110 pre-diagnostic BD patients and 184 controls. We also demonstrated the disease specificity of the panel. CONCLUSIONS: An early and accurate diagnosis has the potential to delay or even prevent the onset of BD. This study demonstrates the potential utility of a biomarker panel as a diagnostic test for BD. We would like to thank all participants of this study as well as all participating centres for the collaboration and for access to the serum samples. We gratefully acknowledge support by the Stanley Medical Research Institute (no. 07R-1888). The infrastructure for the NESDA study (www.nesda.nl) has been funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and participating universities (VU University Medical Center, Leiden University Medical Center, University Medical Center Groningen). DNC, DWN and NSW efforts were funded by the Stanley Medical Research Institute and the US Department of the Army.

Background Since there are few data on the possible association between BDNF levels and characteristics of major depression, the present study assesses brain-derived neurotrophic factor (BDNF) levels in three drug-free patient samples, and explores whether episode duration, and severity correlate with serum BDNF levels. Method Serum BDNF levels were measured in 42 drug-free patients with major depression. The duration of the index episode and the presence of psychotic features were assessed with the Schedule for Affective Disorders and Schizophrenia, and the severity of depression was measured with the 17-item Hamilton Rating Scale for Depression. The sample was divided into three groups: severely depressed inpatients without psychotic features, severely depressed inpatients with psychotic features, and moderately depressed outpatients. Results Mean serum BDNF level in the total sample was 18.0 ± 2.8 ng/ml, with no significant difference between the three patient samples ( F = 1.80, df = 2, p = 0.18). Mean serum BDNF level was significantly lower in patients with an index episode over one year, compared with patients who had a shorter index episode ( F = 4.90, df = 1, p = 0.033). Conclusion These data show that patients with a long index episode have significantly lower serum BDNF levels. We found no influence of the presence of psychotic features and severity of depression on serum BDNF levels.

Genetic variation in AKT1 may be associated with sensitivity to the psychotomimetic effects of cannabis as well as with increased risk for psychotic disorder following cannabis use. Investigation of the effect of this interaction on relevant intermediate phenotypes for psychosis, such as cognition, may help to clarify the underlying mechanism. Thus, verbal memory (visually presented Word Learning Task), sustained attention (Continuous Performance Test, CPT), AKT1 rs2494732 genotype, and cannabis use were examined in a large cohort of patients with psychotic disorder. No evidence was found for AKT1 × cannabis interaction on verbal memory. Cannabis use preceding onset of psychotic disorder did interact significantly with AKT1 rs2494732 genotype to affect CPT reaction time (β=8.0, SE 3.9, p=0.037) and CPT accuracy (β=-1.2, SE 0.4, p=0.003). Cannabis-using patients with the a priori vulnerability C/C genotype were slower and less accurate on the CPT, whereas cannabis-using patients with the T/T genotype had similar or better performance than non-using patients with psychotic disorder. The interaction was also apparent in patients with psychotic disorder who had not used cannabis in the 12 months preceding assessment, but was absent in the unaffected siblings of these patients and in healthy controls. In conclusion, cannabis use before onset of psychosis may have long-lasting effects on measures of sustained attention, even in the absence of current use, contingent on AKT1 rs2494732 genotype. The results suggest that long-term changes in cognition may mediate the risk-increasing effect of the AKT1 × cannabis interaction on psychotic disorder. ispartof: Neuropsychopharmacology vol:36 issue:12 pages:2529-37 ispartof: location:England status: published

Introduction: Immune activation is a characteristic of schizophrenia (SCZ), bipolar disorder (BD) and unipolar major depressive disorder (MDD). The triggering receptor expressed on myeloid cells 1 (TREM-1), its' adaptor molecule DAP12 and their transcription factor (TF) PU.1 are important key genes in inflammation and expressed in activated monocytes and microglia. Aim: To test: (1) if the expressions of TREM-1, DAP12 and PU.1 are increased in monocytes of patients with severe psychiatric disorders and (2) if PU.1 and the TFs ATF3 and EGR3 (which have been found as prominent increased monocyte genes in previous studies) are involved in the regulation of TREM-1 and DAP12 expression. Methods: Using Q-PCR, we studied the gene expression of TREM-1, DAP12, PU.1, ATF3 and EGR3 in the monocytes of 73 patients with severe psychiatric disorders (27 recent onset SCZ patients, 22 BD patients and 24 MDD patients) and of 79 healthy controls (HC). Using in silico TF binding site prediction and in vivo chromatin immunoprecipitation (ChIP), we studied the actual binding of EGR3, ATF3 and PU.1 to the promoter regions of TREM-1 and DAP12. Results: 1. TREM-1 gene expression was increased in the monocytes of SCZ and BD patients and tended to be increased in the monocytes of MDD patients. 2. DAP12 gene levels were neither increased in the monocytes of SCZ, BD, nor MDD patients. 3. PU.1 expression levels were increased in the monocytes of MDD patients, but not in those of SCZ and BD patients. 4. TREM-1 expression levels correlated in particular to ATF3 and EGR3 expression levels, DAP12 expression levels correlated in particular to PU.1 expression levels. 5. We found using binding site prediction and ChIP assays that the TFs EGR3 and ATF3 indeed bound to the TREM-1 promoter, PU.1 bound to both the TREM-1 and DAP12 promoter. Conclusion: In this study, we provide evidence that TREM-1 gene expression is significantly increased in monocytes of SCZ and BD patients and that the TREM-1 gene is a target gene of the TFs ATF3 and EGR3. In MDD patients, PU.1 gene expression was increased with a tendency for TREM-1 gene over expression. Our observations support the concept that monocytes are in a pro-inflammatory state in severe psychiatric conditions and suggest differences in monocyte inflammatory set points between SCZ. BD and MDD. (C) 2011 Elsevier Inc. All rights reserved.

Aims: It has been suggested that schizophrenic patients are more vulnerable to stress than healthy persons, and that stressors can trigger a psychotic episode or worsen symptoms. The biological system often studied in relation to stress is the hypothalamic–pituitary–adrenal (HPA) axis, which controls the release of cortisol. We investigated whether the diurnal basal activity of the HPA axis differed between young male patients with schizophrenia and healthy controls. Methods: Twenty-seven male patients (mean age 22 ± 5 years) and 38 healthy male control subjects (mean age 22 ± 3 years) were included in the present study. Saliva was sampled at five time points during the day: directly after awakening, 30 min thereafter, and at 12.00 hours, 16.00 hours and 22.00 hours. Results: The cortisol concentration decreased significantly more during the day in the patient group thanin the control group. Patients also showed a significantly decreased area under the curve with respect to the increase, again indicating that the cortisol concentrations decreased more during the day in patients than in controls. Both the morning increase and the area under the curve with respect to the increase were significantly negatively correlated with negative symptom severity. Conclusions: Patients with schizophrenia showed a different daytime sensitivity of the HPA axis. Our findings further suggest that an increase in negative symptom severity is related to a decreased HPA axis sensitivity.

Patients with schizophrenia suffer from impairments in facial affect recognition and social functioning. Since antipsychotic medication affects different areas in the brain, they may also affect target areas involved in emotional processing mechanisms. In this article, we review the findings of the effect of antipsychotic medication on facial affect recognition in schizophrenia. We searched PubMed for articles in English with the keywords schizophrenia, facial, affect, emotion, antipsychotic and medication, published till January 2008. Eight relevant articles were found describing original studies. No substantial improvements in facial affect recognition were found after treatment with either typical or atypical antipsychotic drugs. Facial affect recognition was not related to neuropsychological functioning, and it was unclear whether improvement of symptom severity was related to performance on the facial affect recognition tasks. It is recommended that future research should focus on measuring social skills and social functioning more directly, and by investigating the effects of additional behavioural treatments on facial affect recognition and social functioning relative to treatment with antipsychotic medication alone. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Abstract This study aimed to investigate the effects of treatment with haloperidol, olanzapine and risperidone on cardiovascular variability in patients with recent-onset schizophrenia by means of spectral analysis. Unmedicated patients ( n = 18) had a higher mean heart rate and a tendency for a lower high-frequency power of heart rate variability than healthy control subjects ( n = 57), indicating a decreased cardiac vagal control in unmedicated patients with schizophrenia. Patients treated with haloperidol ( n = 10) showed significantly lower low-frequency power of heart rate and systolic blood pressure variability compared with olanzapine-treated patients, suggesting that haloperidol attenuated sympathetic functioning. On the contrary, olanzapine-treated patients ( n = 10) showed the highest power in the low-frequency range of heart rate and systolic blood pressure variability, suggesting an increased sympathetic cardiac functioning. No significant effects of risperidone ( n = 13) were found. None of the antipsychotic agents differed in their parasympathetic cardiovascular effects. We conclude that young, unmedicated patients with schizophrenia differed from controls in their parasympathetic functioning, but the antipsychotic agents haloperidol, risperidone and olanzapine induced only minor cardiovascular side effects.

BACKGROUND: In many scientific disciplines the use of a metaphor as an heuristic aid is not uncommon. A well known example in somatic medicine is the 'defense army metaphor' used to characterize the immune system. In fact, probably a large part of the everyday work of doctors consists of 'translating' scientific and clinical information (i.e. causes of disease, percentage of success versus risk of side-effects) into information tailored to the needs and capacities of the individual patient. The ability to do so in an effective way is at least partly what makes a clinician a good communicator. Schizophrenia is a severe psychiatric disorder which affects approximately 1% of the population. Over the last two decades a large amount of molecular-biological, imaging and genetic data have been accumulated regarding the biological underpinnings of schizophrenia. However, it remains difficult to understand how the characteristic symptoms of schizophrenia such as hallucinations and delusions are related to disturbances on the molecular-biological level. In general, psychiatry seems to lack a conceptual framework with sufficient explanatory power to link the mental- and molecular-biological domains. METHODOLOGY/PRINCIPAL FINDINGS: Here, we present an essay-like study in which we propose to use visualized concepts stemming from the theory on dynamical complex systems as a 'visual metaphor' to bridge the mental- and molecular-biological domains in schizophrenia. We first describe a computer model of neural information processing; we show how the information processing in this model can be visualized, using concepts from the theory on complex systems. We then describe two computer models which have been used to investigate the primary theory on schizophrenia, the neurodevelopmental model, and show how disturbed information processing in these two computer models can be presented in terms of the visual metaphor previously described. Finally, we describe the effects of dopamine neuromodulation, of which disturbances have been frequently described in schizophrenia, in terms of the same visualized metaphor. CONCLUSIONS/SIGNIFICANCE: The conceptual framework and metaphor described offers a heuristic tool to understand the relationship between the mental- and molecular-biological domains in an intuitive way. The concepts we present may serve to facilitate communication between researchers, clinicians and patients.

Several studies have shown that schizophrenic patients have difficulties in their ability to recognize emotional facial expressions, whereas other research indicated that they subjectively report the same emotional experience as healthy controls. The purpose of this study was to investigate whether the physiological responses that accompany emotions differ between schizophrenic patients and controls, which would suggest a different basic emotional processing mechanism in these patients. We presented 40 emotion-eliciting pictures to male patients (n=26) and controls (n=21), while measuring heart rate (HR), breathing rate (BR), skin conductance response (SCR) and systolic blood pressure (SBP). Each subject rated each picture for its degree of valence and arousal. Mixed-effects regression models were used to investigate the relationships between the subjective ratings and the physiological responses. In both groups, BR and SCR increased with increasing arousal ratings, suggesting sympathetic activation. The SBP of both groups increased with increases in both the valence and the arousal ratings. However, whereas the patients' HR first decreased with decreasing pleasure ratings and subsequently increased with higher arousal and valence ratings, the HR in the control group was influenced by a complex interaction between valence and arousal ratings. Thus, the schizophrenic patients showed similar relationships between subjective ratings and SCR, BR, and SBP, but a different relationship between subjective ratings and HR compared with the healthy controls.

In this paper we review the findings on neural growth factors in the peripheral blood of schizophrenia patients. The studies we review provide evidence for the fact that in schizophrenia the levels of growth factors in peripheral blood are disturbed. The most robust results (7 studies) are reported for S100B protein, which seems to be elevated in acute psychosis and in patients with predominant negative symptoms. We conclude that there are aberrant levels of growth factors in peripheral blood in schizophrenia patients, probably most notably in patients with negative symptoms. Large-scale longitudinal multivariate studies, investigating the levels of several growth factors at the same time might give insight in etiological processes and identify clinically useful subsets of patients within the heterogeneous schizophrenia sample.

Although patients with schizophrenia have severe memory impairments and emotional deficits, studies investigating emotional memory modulation (EMM) in schizophrenia show contradictory results, possibly due to methodological differences and small group size. We investigated whether impaired EMM is already present in First Episode Psychosis (FEP) and whether impairments in EMM are task or stimulus dependent Forty-five FEP and thirty-seven Healthy Control (HC) male participants matched for age performed visual and verbal short-term (immediate recall) and long-term (after 24 h recognition) memory tasks with neutral, negative and positive stimuli. On all tasks overall memory performance for FEP was significantly below that of HC. Although EMM varied by task and type of stimulus, none of the tasks showed a difference in EMM between FEP and HC. There were no differences between FEP and HC in the way emotion modulates different memory domains. This could mean that EMM is spared in the early course of schizophrenia. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Schizophrenia is a heterogeneous disorder normally diagnosed using the Diagnostic and Statistical Manual of Mental Disorders criteria. However, these criteria do not necessarily reflect differences in underlying molecular abnormalities of the disorder. Here, we have used multiplexed immunoassay analyses to measure immune molecules, growth factors, and hormones important to schizophrenia in acutely ill antipsychotic-naive patients (n = 180) and matched controls (n = 398). We found that using the resulting molecular profiles, we were capable of separating schizophrenia patients into 2 significantly distinct subgroups with predominant molecular abnormalities in either immune molecules or growth factors and hormones. These molecular profiles were tested using an independent cohort, and this showed the same separation into 2 subgroups. This suggests that distinct abnormalities occur in specific molecular pathways in schizophrenia patients. This may be of relevance for intervention studies that specifically target particular molecular mechanisms and could be a first step to further define the complex schizophrenia syndrome based on molecular profiles.

Alterations of polyunsaturated fatty acids (PUFA) in schizophrenia have been reported, but there is substantial variation in the findings. We performed a systematic review and meta-analysis for docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), linoleic acid (LA), and arachidonic acid (AA). We identified 18 studies which compared PUFA in the erythrocyte cell membrane between patients with schizophrenia and controls. A total of 642 patients (169 were antipsychotic-naïve) and 574 controls participated in these studies. We found suggestive evidence that the levels of DPA (C22:5n3) and DHA (C22:6n3) are decreased both in patients currently being treated with antipsychotic medication and antipsychotic-naïve patients. Our findings furthermore suggest that the levels of LA (C18:2n6) are decreased in the medicated subgroup, but not in the antipsychotic-naive group. Finally, we found decreased levels of AA (C20:4n6), most convincingly in antipsychotic-naive patients. Taken together, there is substantial evidence that decreased levels of DPA (C22:5n3), DHA (C22:6n3), and AA (C20:4n6) are associated with the schizophrenia syndrome, apart from a possible influence of antipsychotic medication. Given the large heterogeneity in results, these conclusions should be interpreted cautiously.

Background Recent studies have suggested that deregulated AKT1 signaling is associated with schizophrenia. We hypothesized that if this is indeed the case, we should observe both decreased AKT1 expression as well as deregulation of AKT1 regulated pathways in Peripheral Blood Mononuclear Cells (PBMCs) of schizophrenia patients. Objectives To examine PBMC expression levels of AKT1 in schizophrenia patients versus controls, and to examine whether functional biological processes in which AKT1 plays an important role are deregulated in schizophrenia patients. Methods/Results A case-control study, investigating whole-genome PBMC gene expression in male, recent onset (

Previous research investigating the emotion recognition ability in patients with schizophrenia has mainly focused on the recognition of facial expressions. To broaden our understanding of emotional processes in patients with schizophrenia, this study aimed to investigate whether these patients experience and process other emotionally evocative stimuli differently from healthy participants. To investigate this, we measured the cardiac and subjective responses of 33 male patients (9 with and 24 without antipsychotic medication) and 40 male control subjects to emotion-eliciting pictures. Cardiac responses were chosen as an outcome measure because previous research has indicated that these are linked with attentional and emotional processes and provide a more objective measure than self-report measures alone. The differences in cardiac responses between patients and controls were limited to medicated patients: only the medicated patients showed significantly decreased cardiac orienting responses compared with control subjects, regardless of picture contents. These results indicate that medicated patients directed less attention towards emotion-eliciting pictures than controls. Decreased attentional resources while processing emotional evocative stimuli could lead to incorrect appraisals of the environment and may have detrimental emotional and social consequences, contributing to chronic stress levels and an increased risk for cardiovascular disease.

We recently described a pro-inflammatory gene expression signature in the monocytes of 60% of patients with recent-onset schizophrenia (SCZ). Here we investigated whether the T-cell system is also in a pro-inflammatory state. A detailed fluorescence-activated cell sorting (FACS) analysis, e. g. of CD3(+) CD25(+) T cells, IFN-gamma(+), IL-4(+), IL-17A(+) (CD4(+)) lymphocytes and CD4(+) CD25(high)FoxP3(+) regulatory T cells, was performed on peripheral blood of 26 patients with recent-onset SCZ (in 19 of whom the inflammatory gene expression signature of the monocyte had been determined) and in age-/gender-matched healthy controls. Various relevant T-cell cytokines, e.g. sCD25, IFN-gamma, IL-17A and IL-4, were measured in serum by a multiplex assay. We detected : (a) not only higher percentages of pro-inflammatory-prone monocytes, activated CD3(+) CD25(+) T cells and pro-inflammatory Th17 cells in patients, but also higher percentages of anti-inflammatory CD4(+) CD25(high)FoxP3(+) regulatory T cells and IL-4(+) lymphocytes; (b) that this activated T-cell set point was reflected in significantly raised serum levels of sCD25; (c) that the up-regulation of IL-4(+)-containing lymphocytes was predominantly found in patients characterized by a monocyte pro-inflammatory set point; and (d) that regulatory T-cell and Th17-cell numbers were higher in patients irrespective of the pro-inflammatory state of the monocytes. Our data do not support the concept that the T-cell system is in a simple pro-inflammatory state in recent-onset SCZ, but do show that the monocyte and T-cell networks are activated and involve both pro-and anti-inflammatory forces. This suggests control within an activated inflammatory system.

There is a major unmet clinical need for molecular blood-based biomarkers in studies of major psychiatric disorders. Thus far, identification of such biomarkers has been sparse, most likely due to the fact that this is reliant on long-standing diagnostic concepts used in psychiatry, which are notoriously heterogeneous. Also, identification of biomarkers for a syndrome that has already been categorized based on clinical phenomenology is not useful in the clinic. This chapter describes the need for innovative approaches for identification of biomarkers which can been used to classify at-risk patients such as youngsters with prodromal symptoms for psychosis and existing patients who are likely to progress to more severe states. The authors argued for the use of broader categories of related patients and to deconstruct the traditional diagnoses in favor of molecular biomarker profiles.

Recently, we showed that the circulating levels of insulin-related peptides and the secretory granule protein chromogranin A were increased in small cohorts of first onset schizophrenia patients. Assuming that this effect was associated with impaired insulin signalling, we investigated the possibility that secretion of other hormones is also affected in schizophrenia. Multiplex immunoassay analysis of 21 hormones and hormone-related molecules was carried out using sera from 236 first and recent onset schizophrenia patients and 230 matched controls. Serum concentrations of insulin and chromogranin A were increased in schizophrenia subjects, consistent with our previous study. In addition, we found elevated concentrations of pancreatic polypeptide, prolactin, progesterone and cortisol, and decreased levels of growth hormone. We also found that growth hormone levels were decreased in post-mortem pituitaries obtained from chronic schizophrenia patients. It will be important to determine whether any of these molecules are involved in the pathosphysiology of schizophrenia or if they reflect the associated insulin resistance. We conclude that function of multiple components of the hypothalamic-pituitary-adrenal-gonadal axis may be affected in schizophrenia. This could have important implications for future biomarker discovery efforts and personalized medicine strategies based on patient stratification for the treatment of this debilitating disorder. (C) 2011 Elsevier Ltd. All rights reserved.

Accumulating evidence indicates an activated inflammatory response system as a vulnerability factor for schizophrenia (SZ) and bipolar disorder (BD). We aimed to detect a specific inflammatory monocyte gene expression signature in SZ and compare such signature with our recently described inflammatory monocyte gene signature in BD. A quantitative-polymerase chain reaction (Q-PCR) case-control gene expression study was performed on monocytes of 27 SZ patients and compared to outcomes collected in 56 BD patients (all patients naturalistically treated). For Q-PCR we used nine 'SZ specific genes' (found in whole genome analysis), the 19 BD signature genes (previously found by us) and six recently described autoimmune diabetes inflammatory monocyte genes. Monocytes of SZ patients had (similar to those of BD patients) a high inflammatory set point composed of three subsets of strongly correlating genes characterized by different sets of transcription/MAPK regulating factors. Subset 1A, characterized by ATF3 and DUSP2, and subset 1B, characterized by EGR3 and MXD1, were shared between BD and SZ patients (up-regulated in 67% and 51%, and 34% and 41%, respectively). Subset 2, characterized by PTPN7 and NAB2 was up-regulated in the monocytes of 62% BD, but down-regulated in the monocytes of 48% of SZ patients. Our approach shows that monocytes of SZ and BD patients overlap, but also differ in inflammatory gene expression. Our approach opens new avenues for nosological classifications of psychoses based on the inflammatory state of patients, enabling selection of those patients who might benefit from an anti-inflammatory treatment.

Objective: To examine whether subjective well-being and craving for cannabis were different in patients with schizophrenia or related disorders treated with either olanzapine or risperidone. Method: A 6-week, double-blind, randomized trial of olanzapine and risperidone was carried out in 128 young adults with recent onset schizophrenia or related disorders. Primary efficacy measures were the mean baseline-to-endpoint change in total scores on the Subjective Well-Being under Neuroleptics scale, the Obsessive–Compulsive Drug Use Scale, the Drug Desire Questionnaire, and the cannabis use self-report. An analysis of covariance was used to test between-group differences. Results: Estimated D2 receptor occupancy did not differ between olanzapine ( n = 63) and risperidone ( n = 65). Similar improvements in subjective well-being were found in both groups. In the comorbid cannabis-using group ( n = 41, 32%), a similar decrease in craving for cannabis was found in both treatment conditions. Conclusions: Both olanzapine and risperidone were associated with improved subjective well-being. No evidence was found for a differential effect of olanzapine or risperidone on subjective experience or on craving for cannabis in dosages leading to comparable dopamine D2 occupancy. Objectif: Examiner si le bien-être subjectif et l'état de manque de cannabis étaient différents chez les patients souffrant de schizophrénie ou de troubles connexes traités à l'olanzapine ou à la rispéridone.

Background: The prevalence of obsessive-compulsive symptoms (OCS) in patients with schizophrenia is relatively high. Antipsychotics have been found to influence OCS. Objective: To determine whether induction or severity of OCS differs during treatment with olanzapine or risperidone in young patients with early psychosis. Methods: One hundred twenty-two patients with a Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder were randomized in a double-blind design to groups of 6 weeks' treatment with olanzapine (n = 59) or risperidone (n = 63), with a mean dose of 11.3 mg olanzapine and 3.0 mg risperidone at 6 weeks. Primary outcome measures were the mean baseline-to-end point change in total score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Results: Treatment with olanzapine was associated with greater decreases in Y-BOCS total score than treatment with risperidone in total group (N = 122: -2.2 vs -0.3, z = -2.651, P < 0.01), in patients with baseline Y-BOCS total score greater than 0 (n = 58: -5.1 vs -0.4, z = -2.717, P < 0.01), and in patients with baseline Y-BOCS total score greater than 10 (n = 29: -7.1 vs -0.6, z = -2.138, P = 0.032). Conclusions: In this randomized, 6-week, double-blind trial, we found a significant and clinically relevant difference in decrease in Y-BOCS scores favoring olanzapine compared with risperidone.

Schizophrenic patients are known to experience difficulties in emotional information processing, yet knowledge of their physiological responsivity to emotional stimuli is limited. The purpose of this study was to investigate the physiological reactions of schizophrenic patients to emotional stimuli. We presented pictures selected from the International Affective Picture System (IAPS) to patients and controls, while assessing their subjective evaluations in terms of valence and arousal scores and measuring their responses of heart rate (HR), breathing rate (BR), skin conductance level (SCL) and diastolic (DBP) and systolic blood pressure (SBP). For the analysis of the physiological data, three emotional picture categories were formed: positive (erotic content), negative (physical injuries) and neutral (landscapes). Patients and controls did not differ in their subjective evaluations of the pictures. Also, for both patients and controls, the SCL and DBP responses to positive emotional pictures were larger as compared to negative and neutral pictures. However, the patients did show significantly increased HR responses to the positive emotional pictures as compared to controls, possibly as a result of a decreased parasympathetic activity. Only for the BR response to the positive emotional pictures did we observe significant positive correlations with the PANSS scores. These first data suggest that altered physiological responsivity to emotional pictures in schizophrenia is limited to those with positive emotional content. Further studies will need to refine the dynamics of this stimulus category in relation to clinical state and medication effects.

BACKGROUND: In schizophrenia, sex specific dimorphisms related to age of onset, course of illness and response to antipsychotic treatment may be mirrored by sex-related differences in the underlying molecular pathways. METHODOLOGY/PRINCIPAL FINDINGS: Here, we have carried out multiplex immunoassay profiling of sera from 4 independent cohorts of first episode antipsychotic naive schizophrenia patients (n = 133) and controls (n = 133) to identify such sex-specific illness processes in the periphery. The concentrations of 16 molecules associated with hormonal, inflammation and growth factor pathways showed significant sex differences in schizophrenia patients compared with controls. In female patients, the inflammation-related analytes alpha-1-antitrypsin, B lymphocyte chemoattractant BLC and interleukin-15 showed negative associations with positive and negative syndrome scale (PANSS) scores. In male patients, the hormones prolactin and testosterone were negatively associated with PANSS ratings. In addition, we investigated molecular changes in a subset of 33 patients before and after 6 weeks of treatment with antipsychotics and found that treatment induced sex-specific changes in the levels of testosterone, serum glutamic oxaloacetic transaminase, follicle stimulating hormone, interleukin-13 and macrophage-derived chemokine. Finally, we evaluated overlapping and distinct biomarkers in the sex-specific molecular signatures in schizophrenia, major depressive disorder and bipolar disorder. CONCLUSIONS/SIGNIFICANCE: We propose that future studies should investigate the common and sex-specific aetiologies of schizophrenia, as the current findings suggest that different therapeutic strategies may be required for male and female patients.