M. Paz García-Portilla

Pro-/Anti-inflammatory Dysregulation in Patients With First Episode of Psychosis: Toward an Integrative Inflammatory Hypothesis of Schizophrenia

BACKGROUND Schizophrenia is a chronic syndrome of unknown etiology, predominantly defined by signs of psychosis. The onset of the disorder occurs typically in late adolescence or early adulthood. Efforts to study pathophysiological mechanisms in early stages of the disease are crucial in order to prompt intervention. METHODS Case-control study of first-episode psychotic (FEP) patients and matched controls. We recruited 117 patients during the first year after their FEP according to the DSM-IV criteria and recruited 106 gender-, race-, and age-matched controls between September 2010 and June 2011. RESULTS Biochemical studies carried out in peripheral mononuclear blood cells (PMBC) and plasma evidence a significant increase in intracellular components of a main proinflammatory pathway, along with a significant decrease in the anti-inflammatory ones. Multivariate logistic regression analyses identified the expression of inducible isoforms of nitric oxide synthase and cyclooxygenase in PMBC and homocysteine plasma levels as the most reliable potential risk factors and the inhibitor of the inflammatory transcription factor NFκB, IκBα, and the anti-inflammatory prostaglandin 15d-PGJ2 as potential protection factors. DISCUSSION Taken as a whole, the results of this study indicate robust phenotypical differences at the cellular machinery level in PMBC of patients with FEP. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways including the activity of nuclear receptors has interesting potential as biological markers and potential risk/protective factors for FEP. Due to its soluble nature, a notable finding in this study is that the anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis.

Association study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia

OBJECTIVE To investigate (i) the association between four serotonergic polymorphisms (A-1438G and T102C of the 5-HT2A receptor gene, and 5-HTT VNTR and 5-HTTLPR of the 5-HT transporter gene) and schizophrenia and (ii) the potential interaction of those polymorphisms in the development of schizophrenia. SUBJECTS AND METHODS 227 outpatients with schizophrenia (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. RESULTS Both groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms are in complete linkage disequilibrium in our population. There was an apparent difference in the distribution of genotypes for the A-1438G (or T102C) polymorphisms (p=0.018, not significant after a Bonferroni correction). The 5-HT2A -1438A (or 102T) allele was significantly more frequent in patients than controls (0.53 and 0.45, respectively; corrected p=0.028, OR=1.39 (95% CI=1.11-1.75)). Genotype and allele distributions for 5-HTT polymorphisms were similar in both groups. However, assessment of the combined influence of 5-HT2A A-1438G and 5-HTTLPR polymorphisms demonstrated a significant effect (chi(2) (3)=11.51, p=0.009), whereby the combination of -1438A and 5-HTTLPR S alleles was associated with schizophrenia. CONCLUSIONS Our findings support a possible synergistic effect of genetic factors influencing serotonergic neurotransmission on susceptibility to schizophrenia.

Functional remediation for patients with bipolar II disorder: Improvement of functioning and subsyndromal symptoms

Recently, Functional Remediation (FR) has proven to be effective in improving the functional outcome of euthymic bipolar patients. The aim of this study was to test the efficacy of the FR program in a subsample of euthymic bipolar II patients (BPII). A post-hoc analyses were undertaken using data of 53 BPII outpatients who had participated in a multicenter, rater-blind, randomized, controlled trial exploring the efficacy of FR (n=17) as compared with a Psychoeducation group (PSY) (n=19) and a treatment as usual control group (TAU n=17). The primary outcome variable was the functional improvement defined as the mean change in the Functioning Assessment Short Test (FAST) from baseline to endpoint after the intervention. Regarding the treatment effect, data reveal a significant functional improvement from baseline to endpoint, suggestive for an interaction between program pertinence and time (pre-post). Nevertheless, Tukey׳s post-hoc test only revealed a trend in favor of a better outcome for FR when compared to the other two groups. We also found an interaction between program pertinence and time when analysing the subdepressive symptoms, with BPII patients in FR showing a significant reduction when compared to the PSY group. Our results suggest that the FR appears to be effective in improving the overall functional outcome in BPII, as well as in reducing subdepressive symptoms.

Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: data from an association study.

OBJECTIVE To investigate the association between dopaminergic polymorphisms [DRD2 -141C Ins/Del, DRD3 Ser9Gly, and SLC6A3 VNTR] and schizophrenia. METHODS Two hundred and eighty-eight outpatients with schizophrenia (DSM-IV criteria) [mean age (SD)=36.4 (12.4), 60.1% males] and 421 unrelated healthy controls [mean age (SD)=40.6 (11.3), 51.3% males] from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS There was a significant difference in genotype distribution for the DRD2 -141C Ins/Del polymorphism [(chi(2) (2)=12.35, corrected p=0.012]. The -141C Del allele was more common in patients than in controls [0.19 vs. 0.13; chi(2) (1)=9.14, corrected p=0.018, OR (95% CI)=1.57 (1.17-2.10)]. Genotype and allele distributions for DRD3 Ser9Gly and SLC6A3 VNTR polymorphisms were similar in both groups. However, there was tentative evidence of an interaction effect between DRD3 Ser9Gly and SLC6A3 VNTR [Wald=9.56 (4), p=0.049]. Compared to the SLC6A3 10/10 genotype category, the risk of schizophrenia was halved among those with 9/10 [OR=0.51 (95% CI=0.30-0.89), p=0.017]. This protective effect was only present in combination with DRD3 Ser/Ser genotype because of the significant interaction between 9/10 and both Ser/Gly [OR=2.45 (95% CI=1.16-5.17), p=0.019] and Gly/Gly [OR=3.80 (95% CI=1.24-11.63), p=0.019]. CONCLUSIONS This study provides evidence that a genetic variant in the DRD2 gene and possible interaction between DRD3 and SLC6A3 genes are associated with schizophrenia. These findings warrant examination in replication studies.

The Incidence of Hospital-Treated Attempted Suicide in Oviedo, Spain

BACKGROUND The incidence of hospital-treated attempted suicide has not been well established in Spain. AIMS To determine the incidence of suicide attempters presenting to a hospital in Oviedo, Spain, to describe the nature of the suicidal behavior, and to identify sociodemographic subgroups of the population with high rates. METHODS All admitted to the Hospital Universitario Central de Asturias, Oviedo, during the period 1 May 2008 to 30 April 2009 were examined and those meeting the internationally-recognized case definition were identified. RESULTS A total of 308 suicide attempt presentations (39% male, 61% female) were made by 279 individuals. Almost 90% of the suicide attempts involved a drug overdose. The age-adjusted total, male, and female attempted suicide rates were 83, 66, and 99 per 100,000, respectively. The highest rate was among 35-44-year-olds for men and women (141.1 and 191.8 per 100,000, respectively). Incidence rates varied widely by sociodemographic characteristics with especially high rates among separated/divorced men (2.4%) and women (1.1%). CONCLUSIONS The reported incidence of hospital-treated attempted suicide is below average in the European context but higher than that reported by previous Spanish studies. Persons separated or divorced constitute a high-risk group.

Ante el nuevo reto de identificar el síndrome negativo de la esquizofrenia

In 2006 the NIMH proposed a Consensus Statement on Negative Symptoms to develop knowledge of the negative dimension of schizophrenia, using a strategy similar to that of the MATRICS project. The consensus (1) established and defined the negative symptoms of schizophrenia, (2) emphasised its situation as a treatment necessity not covered and (3) strongly recommended developing new assessment measures that would solve the significant limitations of the already-existing ones. Since that time, it is accepted that the negative symptoms of schizophrenia are as follows: Social Isolation, Anhedonia, Avolition, Flat affect and Alogia. Apparently there is nothing new under the sun. Back in 1980, T. Crow classified schizophrenia into subtypes I and II based on the predominant symptom, positive or productive as against negative or deficit. In doing so, he again took up the distinction between positive and negative symptoms that De Clérambault had introduced into the world of psychiatry in 1942 without much success. The negative symptoms Crow described were: flattening or blunting of affect, poverty of speech (alogia) or of content, blocking, limited self-care, loss of motivation, anhedonia and social withdrawal. It might be thought that after 25 years of schizophrenia research, the negative syndrome remains anchored in the past, with the same limitations and conceptual difficulties. Although there are still inadequacies,

The course of negative symptoms in first-episode schizophrenia and its predictors: A prospective two-year follow-up study

AIMS This study aimed to investigate the course of negative symptoms and its stability over a two-year period following a first-episode schizophrenia (FES) and the possible predictors of higher severity in this symptomatology after this period. METHODS In this longitudinal two-year prospective follow-up study we included 268 patients with a FES, according to DSM-IV. Analysis of variance was conducted in patients who completed the full follow-up to study changes in negative symptoms over three visits. Regression analyses were conducted to show correlates and potential predictors of negative symptoms at two-year follow-up. RESULTS There was a significant effect for time in negative symptomatology, which was less severe at one-year follow-up after a FES and remained stable up to two years (Time 1>Time 2>Time 3); F(2,151)=20.45, p<0.001. Poorer premorbid adjustment (p=0.01) and higher negative symptoms at baseline (p<0.001) made a significant contribution to the changes in the negative symptoms severity at two-years after a FES (R2=0.21, p<0.001). CONCLUSIONS We found a reduction in the negative symptomatology at one-year after a FES. This change remained stable at two-year. Our results suggested that the presence of this symptomatology early in the course of the illness, together with a poorer premorbid adjustment, predict more severe negative symptoms at mid-term outcome.

Suicidio, desempleo y recesión económica en España

INTRODUCTION The aim of the present work is to determine the association between unemployment and suicide, and to investigate whether this association is affected by changes in the economic cycle or other variables such as age and sex. METHODS A time-trend analysis was conducted to study changes in the number of suicides between 1999 and 2013 in Spain. Pearsons correlation coefficients and regression models were used to find the association between unemployment and suicide. RESULTS A significant positive association was found between unemployment and suicide in the pre-crisis period in men. In that period (1999-2007), each 1% annual increase in unemployment was associated with a 6.90% increase in the annual variation of suicide in the total population, and with a 9.04% increase in the annual variation of suicide in working age men. CONCLUSIONS The correlation between unemployment and suicide is significant in periods of economic stability, but has weakened during the recent financial crisis. Unemployment and suicide have a complex relationship modulated by age, sex and economic cycle.

Do patients with bipolar disorder and subsyndromal symptoms benefit from functional remediation? A 12-month follow-up study

We analyzed the efficacy of functional remediation, in a sample of patients with bipolar disorder who presented with subsyndromal symptoms. From a total sample of 239 patients with bipolar I and II disorder, according to DSM-IV-TR diagnostic criteria, entering a randomized clinical trial, those patients who presented with subsyndromal symptoms were selected based on a method already described by Berk and colleagues was applied. It consists of using the Clinical Global Impression-Bipolar version (CGI-BP) to establish the scores of the Hamilton Depression Rating Scale (HAM-D) and of the Young Mania Rating Scale (YMRS) that correspond with 1 in the CGI-BP. Functional outcome and mood symptoms were assessed at 6 and at 12-month follow-up. A total of 99 patients were selected for this post-hoc analysis, allocated as follows: functional remediation (n=33); psychoeducation (n=37) and treatment as usual (TAU,n=29). The repeated-measures analyses at 12-month follow-up revealed a significant group x time interaction in favour of the patients who received functional remediation when compared to psychoeducation and TAU (F=2.93; p=0.02) at improving psychosocial functioning. Finally, mood symptoms did not significantly change in any of the three groups at any time of follow-up, as shown by the non-significant group x time interaction effect in HAM-D scores (F=1.57; p=0.18) and YMRS scores (F=1.51; p=0.20). Bipolar patients with subsyndromal symptoms improve their functional outcome when exposed to functional remediation regardless of the persistence of mood symptomatology.

Tabaco y rendimiento cognitivo en pacientes con esquizofrenia: diseño del estudio COGNICO

People with schizophrenia constitute a substantial part of the people who still smoke. Regarding cognitive performance, the self-medication hypothesis states that patients smoke to improve their cognitive deficits based on the stimulating effects of nicotine. The aim of this paper is to describe in detail the methodology used in the COGNICO study. A quasi-experimental, observational, prospective, multicenter study with follow-ups over 18 months was conducted in three cities in northern Spain (Oviedo, Ourense and Santiago de Compostela). A total of 81 outpatient smokers with schizophrenia were recruited with a mean age 43.35 years (SD = 8.83), 72.8% of them male. They were assigned to 3 groups: a) control group (smokers); b) patients who quit smoking using nicotine patches; c) patients who quit smoking with Varenicline. The MATRICS neuropsychological battery was applied as a primary measure. In addition, a comprehensive assessment of patients was performed, including the number of cigarettes per day, physical and psychological dependence on nicotine and CO expired. Clinical evaluation (PANSS, HDRS, CGI, C-SSRS), anthropometric measurements and vital signs assessment was also performed. The aim is to identify the relationship between the pattern of tobacco use and cognitive performance by comparing scores on the neuropsychological battery MATRICS during the follow-up periods (3, 6, 12 and 18months). The importance of this study lies in addressing a topical issue often ignored by clinicians: the unacceptably high rates of tobacco use in patients with severe mental disorders.