Paula Suarez-Pinilla

Inverse and direct cancer comorbidity in people with central nervous system disorders: a meta-analysis of cancer incidence in 577,013 participants of 50 observational studies

Background: There is a lack of scientific consensus about cancer comorbidity in people with central nervous system (CNS) disorders. This study assesses the co-occurrence of cancers in patients with CNS disorders, including Alzheimers disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorders, Downs syndrome (DS), Huntingtons disease (HD), multiple sclerosis (MS), Parkinsons disease (PD) and schizophrenia (SCZ). Method: Comprehensive search in PubMed/MEDLINE, Scopus and ISI Web of Knowledge of the literature published before March 2013. We identified 51 relevant articles from 2,229 discrete references, 50 of which contained data suitable for quantitative synthesis (577,013 participants). Pooled effect sizes (ES) were calculated using multiple random-effects meta-analyses. Sources of heterogeneity and uncertainty were explored by means of subgroup and sensitivity analyses, respectively. Results: The presence of CNS disorders was associated with a reduced co-occurrence of cancer (ES = 0.92; 95% confidence interval, CI: 0.87-0.98; I2 = 94.5%). A consistently lower overall co-occurrence of cancer was detected in patients with neurodegenerative disorders (ES = 0.80; 95% CI: 0.75- 0.86; I2 = 82.8%), and in those with AD (ES = 0.32; 95% CI: 0.22-0.46; I2 = 0.0%), PD (ES = 0.83; 95% CI: 0.76-0.91; I2 = 80.0%), MS (ES = 0.91; 95% CI: 0.87-0.95; I2 = 30.3%) and HD (ES = 0.53; 95% CI: 0.42-0.67; I2 = 56.4%). Patients with DS had a higher overall co-occurrence of cancer (ES = 1.46; 95% CI: 1.08-1.96; I2 = 87.9%). No association was observed between cancer and ALS (ES = 0.97; 95% CI: 0.76-1.25; I2 = 0.0%) or SCZ (ES = 0.98; 95% CI: 0.90-1.07; I2 = 96.3%). Patients with PD, MS and SCZ showed (a) higher co-occurrence of some specific cancers (e.g. PD with melanoma, MS with brain cancers and SCZ with breast cancer), and (b) lower co-occurrence of other specific cancers (e.g. lung, prostate and colorectal cancers in PD; lung and prostate cancers in MS; and melanoma and prostate cancer in SCZ). Conclusion: Increased and decreased co-occurrence of cancer in patients with CNS disorders represents an opportunity to discover biological and non-biological connections between these complex disorders.

Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset.

Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86–0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71–0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82–0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset.

Gene-Environment Interactions Underlying the Effect of Cannabis in First Episode Psychosis

Cannabis use may be considered as an additional risk factor in a diathesis-stress model of schizophrenia where the risk of developing the illness would be higher in genetic vulnerable people. In this regard, much of the research on cannabis and psychosis is currently focusing on gene-environment interactions. The present review will focus on the interaction between genes and cannabis exposure in the development of psychotic symptoms and schizophrenia and the biological mechanisms of cannabis. Cannabis use has been shown to act together with other environmental factors such as childhood trauma or urbanicity producing synergistic dopamine sensitization effects. Studies on gene-environment interaction have mainly included genetic variants involved in the regulation of the dopaminergic system. The most promising genetic variants in this field are COMT, CNR1, BDNF, AKT1 and NRG1. Additionally, the interaction with other environmental factors and possible gene-gene interactions are considered in the etiological model.

Prediction of acute clinical response following a first episode of non affective psychosis: Results of a cohort of 375 patients from the Spanish PAFIP study

OBJECTIVE Predicting response to antipsychotic treatment might optimize treatment strategies in early phases of schizophrenia. We aimed to investigate sociodemographic, premorbid and clinical predictors of response to antipsychotic treatment after a first episode of non-affective psychosis. METHOD 375 (216 males) patients with a diagnosis of non affective psychosis entered the study. The main outcome measure was clinical response at 6 weeks and variables at baseline were evaluated as predictors of response. ANOVA for continuous and chi-square for categorical data were used to compare responders and non-responders. Multivariate logistic regression was used to establish a prediction model. RESULTS 53.3% of study subjects responded to antipsychotic treatment. The following variables were associated with an unfavorable response: 1.--lower severity of symptoms at baseline; 2.--diagnosis of schizophrenia; 3.--longer DUI and DUP; 4.--poorer premorbid adjustment during adolescence and adulthood; 5.--family history of psychosis, and 6.--hospitalization. Patients with a family history of psychosis, longer DUP, poor premorbid functioning and lower severity of psychotic symptoms at intake have a reduced likelihood of responding to antipsychotic treatment. CONCLUSION Helping clinicians to identify those first episode patients with a lower probability of having a favorable clinical response is meant as a first step to achieve a successful initial treatment.

Predictors of clinical remission following a first episode of non-affective psychosis: sociodemographics, premorbid and clinical variables.

The aim of the study was to identify predictors associated with a lower likelihood of achieving a clinical remission 1 year after the first break of the illness. Participants were 174 consecutive subjects included in a first episode programme with no prior treatment with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone in a randomized, open-label, prospective clinical trial. The main outcome variable was the remission criteria developed by the Remission in Schizophrenia Working Group. Clinical variables were included in a logistic regression analysis in order to predict the remission state at 1 year. At 1 year, 31% of patients met criteria for remission. The logistic regression analysis revealed that the strongest predictors of achieving clinical remission 1 year away from a first episode of non-affective psychosis were the length of duration of untreated psychosis (DUP), the severity of negative symptomatology and the educational level attained at baseline. The results suggest that: (1) patients with a lengthy DUP, a greater severity of negative symptomatology at baseline and with a lower education level are in a higher risk of not achieving a clinical remission during the first year of treatment; and (2) early intervention clinical programs should aim to reduce the length of DUP in order to provide a better outcome for patients.

Comparison of metabolic effects of aripiprazole, quetiapine and ziprasidone after 12 weeks of treatment in first treated episode of psychosis

This randomized open-label study compared the incidence of metabolic side effects of aripiprazole, ziprasidone and quetiapine in a population of medication-naïve first-episode psychosis patients. A total of 202 subjects were enrolled. Body weight, body mass index, leptin, fasting lipids and fasting glycaemic parameters were measured at baseline and at 3 months follow-up. A hundred and sixty-six patients completed the follow-up and were included in the analyses. A high proportion of patients experienced a significant weight increase (>7% of their baseline weight): 23% ziprasidone (n=12), 32% with quetiapine (n=16) and 45% with aripiprazole (n=31). Patients treated with aripiprazole gained significantly more weight than the patients in the ziprasidone group (1.2 kg [SD=4.1] versus 4.3 kg [SD=4.8], respectively). The increase in leptin levels was greater in women treated with aripiprazole than in those treated with ziprasidone (p=0.030). Mean prolactin levels significantly increased in patients treated with quetiapine and ziprasidone but not in those treated with aripiprazole. Patients treated with quetiapine and aripiprazole showed a significant increase in total cholesterol and LDL-cholesterol plasma levels. Quetiapine-treated patients resulted in a higher increase in LDL-cholesterol than patients treated with ziprasidone (p=0.021). No other significant differences between groups were found. No significant changes in glycaemic parameters were observed. Our results suggest that ziprasidone has a lower liability for inducing weight gain and lipid abnormalities than aripiprazole or quetiapine.

Aripiprazole, Ziprasidone and Quetiapine in the treatment of first-episode nonaffective psychosis: A 12-week randomized, flexible-dose, open-label trial

BACKGROUND Differences among antipsychotics in terms of effectiveness have turned out to be a topic of increasing research interest, although comparisons between the different second generation antipsychotics (SGAs) are scarce. We aimed to compare the clinical effectiveness in the short-term of Aripiprazole, Ziprasidone and Quetiapine in the treatment of first-episode schizophrenia-spectrum disorders. METHOD From October 2005 to January 2011, a prospective, randomized, open-label study was undertaken. 202 first-episode drug-naïve patients were randomly assigned to Aripiprazole (N = 78), Ziprasidone (N = 62), or Quetiapine (N = 62) and followed-up for 3 months. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on intention-to-treat populations was conducted in the analysis for clinical efficacy. RESULTS The overall dropout rate at 3 months was small (13.86%). The treatment discontinuation rate differed significantly between treatment groups (Aripiprazole = 23.1%, Ziprasidone = 37.1% and Quetiapine = 61.3%) (χ(2) = 21.334; p < 0.001). Insufficient efficacy in the group of Quetiapine is the main reason for discontinuation rate differences (χ(2) = 20.223; p < 0.001). The mean time to all-cause discontinuation was significantly different between groups (LogRank = 23.467 p < 0.001). Aripiprazole and Quetiapine were associated with a greater depressive symptoms improvement (p = 0.043). The profile of side-effects varies between treatments. Patients on Quetiapine were less likely to be prescribed hypnotics. CONCLUSIONS Patients treated with Quetiapine had a higher risk of treatment discontinuation in the short-term after a first episode due to insufficient efficacy. Establishing differences between SGAs may help clinicians in prescribing decisions for the treatment of individuals presenting with first-episode schizophrenia.

Brain structural and clinical changes after first episode psychosis: Focus on cannabinoid receptor 1 polymorphisms

Cannabinoid receptor 1 (CNR1) gene polymorphisms have been associated with central and peripheral effects of cannabis and schizophrenia pathophysiology. Here, we have tested whether three CNR1 variants (rs1049353, rs1535255 and rs2023239) are associated with changes in brain volumes, body mass index (BMI) or psychopathological scores in a 3-year longitudinal study of 65 first-episode psychosis patients. The rs1049353 at-risk allele was significantly associated with a greater reduction of caudate volume, and the rs2023239 T/C polymorphism showed a significant decrease in thalamic volume after the 3-year period. For those who were not cannabis users, the rs1535255 and rs2023239 polymorphisms had effects in lateral ventricle (LV), and LV and white matter, respectively. The rs2023239 variant also was associated with significant improvements in positive and negative symptoms of schizophrenia. There was no significant effect of any of the variants on changes in BMI over the 3-year study. Finally, an interaction between all three polymorphisms was found involving evolution of positive symptoms. These findings suggest that the cannabinoid pathway is associated with schizophrenia evolution over time. However, further studies using larger cohorts are needed to confirm these results. If confirmed, the present findings could lead in subsequent investigations for identification of novel drug targets for improved treatment of patients suffering from schizophrenia.

Brain Structural Effects of Antipsychotic Treatment in Schizophrenia: A Systematic Review.

The findings about the progressive brain changes in schizophrenia are controversial, and the potential confounding effect of antipsychotics on brain structure is still under debate. The goal of the current article was to review the existing longitudinal neuroimaging studies addressing the impact of antipsychotic drug treatment on brain changes in schizophrenia. A comprehensive search of PubMed was performed using combinations of key terms distributed into four blocks: “MRI”, “longitudinal”, “schizophrenia” and “antipsychotic”. Studies were considered to be eligible for the review if they were original articles. Studies that examined only changes in brain density were excluded. A total of 41 MRI studies were identified and reviewed. Longitudinal MRI studies did not provide a consistent notion of the effects of antipsychotic treatment on the pattern of brain changes over time in schizophrenia. Overall, most of the included articles did not find a linear relationship between the degree of exposure and progressive brain changes. Further short- and longterm studies are warranted to a better understanding of the influence of antipsychotics in brain structural changes in schizophrenia and also to verify whether first and second generation antipsychotics may differentially affect brain morphometry.

Grey matter volume differences in non-affective psychosis and the effects of age of onset on grey matter volumes: A voxelwise study

Previous evidence indicates that structural brain alterations are already present in the early phases of psychosis. In this study we aim to investigate the relationships among the different diagnoses in the spectrum of non-affective psychosis. A hundred-and-one first-episode psychosis patients (FEP) and 69 healthy volunteers, matched for age, gender, handedness and educational level were analyzed by structural MRI and high-dimensional voxel-based morphometry as implemented in SPM8 software. We obtained three main results: (1) FEP patients showed reduction of grey matter volume (GMV) in the frontal, temporal and occipital lobes, left insula and cerebellum. (2) Age of disease onset was an important factor revealing a gradual decrease of GMV (healthy controls>late onset>intermediate onset>early onset) in the frontal, temporal and occipital lobes, insula and cerebellum. (3) A gradual reduction of GMV related to diagnosis spectrum in the frontal, temporal, parietal and occipital lobes of schizophrenia patients being the most affected. These results suggest that an earlier onset of psychosis is linked to an earlier disease-related disruption of structural brain development, which may be most pronounced in schizophrenia compared to other psychoses.