Pretreatment levels of the fatty acid handling proteins H-FABP and CD36 predict response to olanzapine in recent-onset schizophrenia patients.

Traditional schizophrenia pharmacotherapy remains a subjective trial and error process involving administration, titration and switching of drugs multiple times until an adequate response is achieved. Despite this time-consuming and costly process, not all patients show an adequate response to treatment. As a consequence, relapse is a common occurrence and early intervention is hampered. Here, we have attempted to identify candidate blood biomarkers associated with drug response in 121 initially antipsychotic-free recent-onset schizophrenia patients treated with widely-used antipsychotics, namely olanzapine (n=40), quetiapine (n=23), risperidone (n=30) and a mixture of these drugs (n=28). Patients were recruited and investigated as two separate cohorts to allow biomarker validation. Data analysis showed the most significant relationship between pre-treatment levels of heart-type fatty acid binding protein (H-FABP) and response to olanzapine (p=0.008, F=8.6, β=70.4 in the discovery cohort and p=0.003, F=15.2, β=24.4 in the validation cohort, adjusted for relevant confounding variables). In a functional follow-up analysis of this finding, we tested an independent cohort of 10 patients treated with olanzapine and found that baseline levels of plasma H-FABP and expression of the binding partner for H-FABP, fatty acid translocase (CD36), on monocytes predicted the reduction of psychotic symptoms (p=0.040, F=6.0, β=116.3 and p=0.012, F=11.9, β=-0.0054, respectively). We also identified a set of serum molecules changed after treatment with antipsychotic medication, in particular olanzapine. These molecules are predominantly involved in cellular development and metabolism. Taken together, our findings suggest an association between biomarkers involved in fatty acid metabolism and response to olanzapine, while other proteins may serve as surrogate markers associated with drug efficacy and side effects.This work was supported by the Stanley Medical Research Institute (SMRI); the European Union FP7 SchizDX research programme (grant reference 223427); the European Union FP7 funding scheme: Marie Curie Actions Industry Academia Partnerships and Pathways (nr. 286334, PSYCH-AID project); by the Virgo consortium, funded by the Dutch Government (project number FES0908); by the Netherlands Genomics Initiative (project number 050-060-452); by the Dutch Fund for Economic Structure Reinforcement, the NeuroBasic PharmaPhenomics project (no. 0908) and by the Engineering and Physical Sciences Research Council UK (EPSRC CASE studentship and Impact Acceleration Award).This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.bbi.2015.10.01

Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model.

The phosphoinositide-3-kinase (PI3K) family plays a major role in cell signaling 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 p110δE1020K 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

Multimodel inference for biomarker development: an application to schizophrenia.

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

Validation of a Blood-Based Laboratory Test to Aid in the Confirmation of a Diagnosis of Schizophrenia

We describe the validation of a serum-based test developed by Rules-Based Medicine which can be used to help confirm the diagnosis of schizophrenia. In preliminary studies using multiplex immunoassay profiling technology, we identified a disease signature comprised of 51 analytes which could distinguish schizophrenia (n = 250) from control (n = 230) subjects. In the next stage, these analytes were developed as a refined 51-plex immunoassay panel for validation using a large independent cohort of schizophrenia (n = 577) and control (n = 229) subjects. The resulting test yielded an overall sensitivity of 83% and specificity of 83% with a receiver operating characteristic area under the curve (ROC-AUC) of 89%. These 51 immunoassays and the associated decision rule delivered a sensitive and specific prediction for the presence of schizophrenia in patients compared to matched healthy controls

Effect of olanzapine and risperidone on subjective well-being and craving for cannabis in patients with schizophrenia or related disorders: a double-blind randomized controlled trial

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 D(2) 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 D(2) occupancy. Clinical Trial Registration Number: ISRCTN4636599

Analysis of pathogenic autoantibodies against the N-methyl-D-aspartate glutamate receptor in schizophrenia

status: publishe