Isabel Martínez-Gras

Modulation of impulsivity by topiramate: implications for the treatment of alcohol dependence.

Topiramate (TP), an anticonvulsant drug, has been widely used in the treatment of disorders characterized by impulsivity symptoms, so it goes to reason that it might be useful in addictive disorders. Recently, TP has been used to treat alcohol dependence, but it is still not known whether the effects of TP on alcohol consumption are related with its action on impulsivity. The aim of this preliminary study was to investigate which dimension of behavioral impulsivity is associated with the effects of TP. A 12-week, double-blind, placebo-controlled pilot study of TP for the treatment of alcohol dependence was conducted. Subjects were men recruited from alcoholism treatment units (TP = 31; placebo = 32). Diagnoses were made using the Structured Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Behavioral inhibition was assessed using the continuous performance test (CPT) and the stop-signal task. Differential reinforcement for low-rate responding (DRLR) was used to evaluate the delay-discounting dimension. Alcohol craving and alcohol consumption during the study were evaluated. Patients treated with TP presented lower rates of alcohol consumption in the number of drinks per drinking day (P < 0.05) and the number of heavy drinking days (P < 0.001). Scores on alcohol craving scales decreased significantly, and there was more improvement on the continuous performance test (total omissions and total commissions) and on the stop-signal task in the TP group than in the control group. Improved alcohol consumption behavior was associated with performance on the behavioral inhibition paradigm. The results of this study indicate that TP reduces drinking and that the mechanisms underlying this effect may involve, at least in part, modulation of the behavioral inhibition paradigm.

The anti-inflammatory prostaglandin 15d-PGJ2 and its nuclear receptor PPARgamma are decreased in schizophrenia

A number of findings suggest that inflammation plays a role in the pathophysiology of schizophrenia. Taking into account a physiological balance between pro- and anti-inflammatory mediators, we measured the plasma levels of cyclooxygenase-derived mediators and other key pro- and anti-inflammatory transcription factors in peripheral blood mononuclear cells (PBMC). Forty healthy subjects and 46 treated chronic schizophrenic patients with an acutely exacerbated condition who met DSM-IV criteria were included. COX by-products prostaglandin E2 (PGE2) and 15d-prostaglandin J2 (15d-PGJ2) plasma levels were measured by EIA. Peroxisome proliferator-activated receptor gamma (PPARγ) as well as nuclear factor kappaB (NFκB) activity in nuclear extracts from PBMC and expression of its inhibitory subunit IκBα in cytosolic extracts were determined using ELISA-based kits. Schizophrenic patients showed higher plasma levels of pro-inflammatory PGE2 than age-matched controls (p=0.043). On the contrary, levels of anti-inflammatory 15-d-PGJ2 were lower (p=0.004), correlating with a lower expression of its nuclear target, PPARγ in nuclear extracts from PBMC (p=0.001). Although no changes in NFκB activity were observed between patients and healthy controls, the expression of its inhibitory protein IκBα was lower in the patients compared to the controls (p=0.027). These findings suggest that schizophrenia is associated with a systemic imbalance in the plasma levels of pro-inflammatory/anti-inflammatory prostaglandins in favor of the former. Furthermore, the expression and activity of anti-inflammatory PPARγ are diminished in PBMC, which indicates a state of inflammation and blunted anti-inflammatory counterbalancing mechanisms at systemic level in these patients.

Cognition and the five-factor model of the Positive and Negative Syndrome Scale in schizophrenia

Different exploratory and confirmatory factorial analyses of the Positive and Negative Syndrome Scale (PANSS) have found a number of factors other than the original positive, negative, and general psychopathology. Based on a review of previous studies and using confirmatory factor analyses (CFA), Wallwork et al. (Schizophr Res 2012; 137: 246-250) have recently proposed a consensus five-factor structure of the PANSS. This solution includes a cognitive factor which could be a useful measure of cognition in schizophrenia. Our objectives were 1) to study the psychometric properties (factorial structure and reliability) of this consensus five-factor model of the PANSS, and 2) to study the relationship between executive performance assessed using the Wisconsin Card Sorting Test (WCST) and the proposed PANSS consensus cognitive factor (composed by items P2-N5-G11). This cross-sectional study included a final sample of 201 Spanish outpatients diagnosed with schizophrenia. For our first objective, CFA was performed and Cronbachs alphas of the five factors were calculated; for the second objective, sequential linear regression analyses were used. The results of the CFA showed acceptable fit indices (NNFI=0.94, CFI=0.95, RMSEA=0.08). Cronbachs alphas of the five factors were adequate. Regression analyses showed that this five-factor model of the PANSS explained more of the WCST variance than the classical three-factor model. Moreover, higher cognitive factor scores were associated with worse WCST performance. These results supporting its factorial structure and reliability provide robustness to this consensus PANSS five-factor model, and indicate some usefulness of the cognitive factor in the clinical assessment of schizophrenic patients.

The relationship between prepulse inhibition and general psychopathology in patients with schizophrenia treated with long-acting risperidone

Patients with schizophrenia exhibit impairments in prepulse inhibition (PPI) of the startle response. Available data suggest that atypical antipsychotics may be more effective than typical antipsychotics in improving PPI deficits in schizophrenia. However, previous studies have used between-subjects rather than longitudinal within-subjects designs to demonstrate superiority of particular atypical antipsychotics over typical antipsychotics in improving PPI in patients with schizophrenia. This longitudinal within-subjects test-retest study was designed to evaluate changes in PPI and clinical symptoms in patients with schizophrenia after switching from the conventional antipsychotic zuclopenthixol to long-acting injectable risperidone. PPI was measured in 45 chronic male patients with schizophrenia treated with zuclophentixol depot (session T1), and 12 weeks after switching to long-acting injectable risperidone (session T2). Thirty-six healthy control subjects were also evaluated. Patients with schizophrenia showed a significant improvement in PPI after changing to long-acting risperidone. Improvement of PPI deficits between T1 and T2 assessments correlated significantly with improvements in PANSS general psychopathology subscale scores. Our findings indicate that long-acting risperidone improves PPI deficits in subjects with chronic schizophrenia. These results also suggest that the PPI-restoring effect of risperidone may be related to improvement in symptoms other than positive and negative symptoms.

Differential dorsolateral prefrontal cortex activation during a verbal n-back task according to sensory modality

Functional neuroimaging studies carried out on healthy volunteers while performing different n-back tasks have shown a common pattern of bilateral frontoparietal activation, especially of the dorsolateral prefrontal cortex (DLPFC). Our objective was to use functional magnetic resonance imaging (fMRI) to compare the pattern of brain activation while performing two similar n-back tasks which differed in their presentation modality. Thirteen healthy volunteers completed a verbal 2-back task presenting auditory stimuli, and a similar 2-back task presenting visual stimuli. A conjunction analysis showed bilateral activation of frontoparietal areas including the DLPFC. The left DLPFC and the superior temporal gyrus showed a greater activation in the auditory than in the visual condition, whereas posterior brain regions and the anterior cingulate showed a greater activation during the visual than during the auditory task. Thus, brain areas involved in the visual and auditory versions of the n-back task showed an important overlap between them, reflecting the supramodal characteristics of working memory. However, the differences found between the two modalities should be considered in order to select the most appropriate task for future clinical studies.

Altered immune function in unaffected first-degree biological relatives of schizophrenia patients

Inflammatory and immune processes have been implicated in the etiopathology of schizophrenia. We demonstrate the existence of immune function alteration, assessed by serum cytokines levels, not only in schizophrenia patients but also in their unaffected first-degree relatives. This finding may provide a new data for considering cytokines as schizophrenic disease biomarkers.

Effects of zonisamide in the treatment of alcohol dependence.

Objective:Anticonvulsant drugs have been used in the treatment of alcohol dependence. The purpose of the present study was to evaluate tolerance and safety of zonisamide in a sample of patients presenting alcohol dependence. Methods:Open-label zonisamide was examined in 22 outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol dependence. Zonisamide was started at a dose of 50 mg/d and titrated to a maximun dose of 300 mg/d. Subjects received a baseline evaluation including Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and the Severity of Alcohol Dependence Scale. Alcohol craving and alcohol consumption were assessed at weeks 2, 4, 6, 8, 10, and 12. The concentration of &ggr;-glutamyltransferase was used as an indirect measure of alcohol consumption. Results:Significant improvement was observed in visual analog scale for craving severity scores, weekly drink consumption, and &ggr;-glutamyltransferase. Zonisamide was well tolerated, with only a dropout due to adverse events. Conclusions:Zonisamide is safe and well tolerated in this sample and associated with improvement in alcohol craving and alcohol consumption. A placebo-controlled study would be of interest.

Negative Symptoms and Executive Function in Schizophrenia: Does Their Relationship Change with Illness Duration?

Background: Negative symptoms and cognitive dysfunction are of crucial functional and prognostic importance in schizophrenia. However, the nature of the relationship between them and the factors that may influence it have not been well established. Aims: To investigate whether the relationship between negative symptoms and executive function changes according to the duration of illness in schizophrenia. Methods: The Positive and Negative Syndrome Scale was used to assess psychopathology and the Wisconsin Card Sorting Test (WCST) to evaluate executive function in a sample of 200 schizophrenic patients who were classified in 3 groups according to their duration of illness: up to 5 years (short duration group), 6-20 years (intermediate duration group) and over 20 years of illness (long duration group). Results: Medium-sized correlations were found between negative symptoms and WCST performance as assessed by the number of completed categories in all 3 groups. However, differences were found according to the duration of schizophrenia. For patients in the short duration group, negative symptoms correlated with WCST nonperseverative errors, but for those in the long duration group the correlation was with perseverative errors. Conclusion: We found a differential relationship between negative and cognitive symptoms in different stages of schizophrenia. Illness duration should be considered when studying the relationship between negative symptoms and cognition.

Executive function in schizophrenia: Influence of substance use disorder history

Cognitive function in schizophrenia has been associated with different sociodemographic and clinical variables. Substance use disorder (SUD) history has also been associated with cognition in schizophrenia; however, contradictory results have been found regarding its influence on cognitive function. Our aim was to study the relationship between executive function and a) age, b) duration of illness, c) number of psychotic episodes, d) positive symptoms, and e) negative symptoms, in a sample of schizophrenic patients, and secondly to study whether these relationships persisted after stratification of the sample according to the presence or absence of SUD history. A final sample of 203 schizophrenic patients were evaluated for psychotic symptoms using the PANSS, and assessed using a neuropsychological battery to calculate a composite executive function score. Linear regression analyses were performed, with this executive score as the dependent variable, and age, duration of illness, number of psychotic episodes, positive PANSS score and negative PANSS score as independent variables. For the total sample, the regression model showed three variables to be significant predictors of the executive score: age (p=0.004), number of episodes (p=0.027), and PANSS negative score (p=0.003). However, once the sample was stratified, the regression model showed age (p=0.011) and number of episodes (p=0.011) to be predictor variables for the executive score in the group of schizophrenic patients with SUD history, while age (p=0.028) and PANSS negative score (p=0.006) were predictors in the group of schizophrenic patients without such history. These findings highlight the importance of considering SUD history in studies of cognitive function in schizophrenia.

Increased vulnerability to ethanol consumption in adolescent maternal separated mice.

The purpose of this study was to evaluate the effects of early life stress on the vulnerability to ethanol consumption in adolescence. To this aim, mice were separated from their mothers for 12 hours/day on postnatal days 8 and 12. Emotional behavior (light‐dark box, elevated plus maze and tail suspension tests) and pre‐attentional deficit (pre‐pulse inhibition) were evaluated in adolescent maternal separated (MS) mice. Alterations of the corticotropin‐releasing factor (CRF), glucocorticoid receptor (NR3C1), tyrosine hydroxylase (TH), mu‐opioid receptor (MOr), brain‐derived neurotrophic factor (BDNF), neuronal nuclei (NeuN), microtubule‐associated protein 2 (MAP2) and neurofilament heavy (NF200)‐immunoreactive fibers were studied in the paraventricular nucleus of the hypothalamus (PVN), ventral tegmental area (VTA), nucleus accumbens (NAc) or hippocampus (HIP). The effects of maternal separation (alone or in combination with additional stressful stimuli) on ethanol consumption during adolescence were evaluated using the oral ethanol self‐administration paradigm. MS mice presented mood‐related alterations and pre‐attentional deficit. Increased CRF, MOr and TH, and reduced BDNF, NR3C1, NeuN, MAP2 and NF200‐immunoreactive fibers were observed in the PVN, NAc and HIP of adolescent MS mice. In the oral ethanol self‐administration test, adolescent MS mice presented higher ethanol consumption and motivation. Exposure to additional new stressful stimuli during adolescence significantly increased the vulnerability to ethanol consumption induced by maternal separation. These results clearly demonstrated that exposure to early life stress increased the vulnerability to ethanol consumption, potentiated the effects of stressful stimuli exposure during adolescence on ethanol consumption and modified the expression of key targets involved in the response to stress, ethanol reinforcing properties and cognitive processes.