Greater clinical and cognitive improvement with clozapine and risperidone associated with a thinner cortex at baseline in first-episode schizophrenia.

Cortical thickness may be useful as a treatment response predictor in first-episode (FE) patients with schizophrenia, although this possibility has been scarcely assessed. In this study we assessed the possible relation between cortical thickness in regions of interest selected because of previously reported structural alterations in schizophrenia and clinical and cognitive changes after two years of treatment with risperidone or clozapine in 31 neuroleptic-naïve FE patients with schizophrenia (16 of them treated with clozapine and 15 with risperidone). Using the last-observation-carried-forward (LOCF), a larger improvement in positive, negative and total symptoms was predicted by the amount of baseline cortical thinning in the right prefrontal cortex (pars orbitalis). After two years of treatment, cognitive status was reassessed in the 17 patients (11 on clozapine) who had not dropped out. Working memory improvement after reassessment was associated with a greater baseline cortical thinning in the left prefrontal cortex (pars orbitalis), and verbal memory improvement with a greater baseline cortical thinning in the left pars triangularis. Significant but weak cortical thickness decrease from baseline to follow-up was observed in patients in comparison to controls (left pars triangularis and opercularis, and left caudal middle frontal areas). These results may support a positive predictive role for cortical thinning in the frontal region with regard to clinical and cognitive improvement with clozapine and risperidone in FE patients with schizophrenia.

Randomized trial of clozapine vs. risperidone in treatment-naïve first-episode schizophrenia: results after one year.

In first-episode patients with psychosis, clozapine may be potentially valuable as an initial treatment seeking to limit early on clinical and cognitive deterioration. Nevertheless, until recently its restricted use has limited the study of this possibility. Our research group is developing a non-commercial, multicentric and open label study on the differential efficacy between clozapine and risperidone in first-episode schizophrenia. In this paper, we present the results related to clinical variables after a one-year follow-up. So far, we have recruited 30 patients diagnosed with schizophrenia or schizophreniform disorder with illness duration of less than two years. The patients had not received any previous treatment and they were randomized to treatment with clozapine or risperidone. Our results indicate that on average, patients on clozapine adhered to their original treatment for a longer time period than patients on risperidone. By last observation carried forward (LOCF) analysis, patients on clozapine and risperidone displayed similar clinical improvements, although marginally greater improvements in positive and total symptoms scores were found in the clozapine group. At the 12-month point we observed a marginal improvement in negative symptom scores in patients on clozapine. Subjective secondary effects, as measured with the Udvalg for KliniskeUndersøgelser (UKU) scale, correlated negatively with negative symptoms at follow-up. Our data, although preliminary, suggest that clozapine may have a slightly superior efficacy in the initial year of treatment of first-episode treatment-naïve patients with schizophrenia, and this can be explained for the most part by greater adherence to this treatment.

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.

Gender-specific COMT Val158Met polymorphism association in Spanish schizophrenic patients.

The functional Val158Met polymorphism (rs4680) located at the gene that codes for the catechol-O-methyltransferase (COMT) has been extensively investigated in schizophrenia although current data are still controversial. Since COMT activity is sexually dimorphic, we carried out two independent studies in homogeneous samples of male and female Spanish schizophrenic patients. In males, we found an association between the homozygous Val genotype and the disorder, which resembled a recessive model (P = 0.022; odds ratio [OR] = 1.67). This Val homozygotes overrepresentation is produced at the expense of the heterozygous individuals decrease, whilst the Met homozygotes showed no differences when compared controls and patients. As a consequence, the heterozygous genotype in this sample had a protective effect (P = 0.03; OR = 0.65) and a strong deviation from Hardy-Weinberg equilibrium in male cases was observed (P = 0.006). In addition, a 2-SNP haplotype analysis (rs4818-Val158Met) confirmed there is an overrepresentation of the different homozygous Val genotypes in the male schizophrenic sample. Regarding females, we did not find any statistically significant association between COMT SNP and schizophrenia. In the light of this we suggest that the Val158Met SNP is involved in risk and protective genotypes for the vulnerability to schizophrenia in Spanish male population.

The ANKK1 kinase gene and psychiatric disorders.

The TaqIA single nucleotide polymorphism (SNP, rs1800497), which is located in the gene that codes for the putative kinase ANKK1 (ANKK1) near the termination codon of the D2 dopamine receptor gene (DRD2; chromosome 11q22-q23), is the most studied genetic variation in a broad range of psychiatric disorders and personality traits. A large number of individual genetic association studies have found that the TaqIA SNP is linked to alcoholism and antisocial traits. In addition, it has also been related to other conditions such as schizophrenia, eating disorders, and some behavioral childhood disorders. The TaqIA A1 allele is mainly associated with addictions, antisocial disorders, eating disorders, and attention-deficit/hyperactivity disorders, while the A2 allele occurs more frequently in schizophrenic and obsessive-compulsive patients. Current data show that the TaqIA polymorphism may be a marker of both DRD2 and ANKK1 genetic variants. ANKK1 would belong to a family of kinases involved in signal transduction. This raises the question of whether signaling players intervene in the pathophysiology of psychiatric disorders. Basic research on the ANKK1 protein and its putative interaction with the D2 dopamine receptor could shed light on this issue.

[Dual diagnosis in psychiatric inpatients: prevalence and general characteristics]. / Patología dual en pacientes psiquiátricos hospitalizados: prevalencia y características generales.

Comorbidity between a substance use disorder (SUD) and another psychiatric disorder is known as dual diagnosis. It is of great relevance due to its important clinical consequences and costs of care. There are practically no published studies on dual diagnosis prevalence in patients admitted to psychiatric hospitalization units in general hospitals (PHUGH) in our country. The objectives were to estimate the prevalence of dual diagnosis in psychiatric inpatients admitted consecutively to a Psychiatric Hospitalization Unit (Hospital Universitario 12 de Octubre, Madrid, Spain) in one year, to compare clinical and sociodemographic variables between the dual diagnosis group (DD group) and the group with a psychiatric disorder but no SUD (PD group), and to study the types of substances used. This is a retrospective study, based on the review of the clinical charts of the 257 patients admitted to this PHUGH in one year. The results showed that, excluding nicotine dependence, 24.9% of our inpatients had a SUD as well as another psychiatric disorder. A statistically significant predominance of men was found in the DD group, as well as a younger age at the time of the study, at the beginning of their psychiatric attention and on their first psychiatric admission, and they had received diagnoses of schizophrenia or related psychoses more often than the PD group, who had mostly affective disorders. The substances most frequently used in the DD group were alcohol (78.1%), cannabis (62.5%), and cocaine (51.6%). Due to the high prevalence and repercussions of dual diagnosis, it would be advisable to have specialized therapeutic programs for its treatment.

Patología dual en pacientes psiquiátricos hospitalizados: prevalencia y características generales / Dual diagnosis in psychiatric inpatients: prevalence and general characteristics

La comorbilidad entre un trastorno por uso de sustancias (TUS) y otros trastornos psiquiátricos es conocida como patología dual. Tiene gran relevancia por su repercusión clínica y coste asistencial. Apenas existen estudios en nuestro medio sobre prevalencia de patología dual en pacientes ingresados en unidades de hospitalización psiquiátrica de hospitales generales (UHPHG). Los objetivos de este trabajo fueron determinar la presencia de patología dual en los pacientes ingresados consecutivamente durante un año en una Unidad de hospitalización Psiquiátrica (Hospital Universitario 12 de Octubre, Madrid, España), comparar variables sociodemográficas y clínicas entre el grupo de patología dual (grupo PD) y el grupo de trastorno mental sin TUS concurrente (grupo TM), y estudiar el tipo de sustancias consumidas. Se trata de un estudio retrospectivo, basado en la revisión de las historias clínicas de los 257 pacientes ingresados en dicha UHPHG durante un año. Los resultados mostraron que el 24,9 por ciento de los pacientes ingresados presentó un TUS (excluyendo dependencia a nicotina) concurrente a otro trastorno psiquiátrico. De manera significativa los pacientes del grupo PD fueron predominantemente varones y más jóvenes. Además, tenían menor edad en el primer ingreso psiquiátrico y al inicio de recibir atención psiquiátrica, y presentaban más diagnósticos de esquizofrenia o psicosis esquizofreniforme que el grupo TM, este último caracterizado por mayor frecuencia de diagnósticos afectivos. Las sustancias más frecuentemente consumidas en el grupo PD fueron alcohol (78,1 por ciento), cannabis (62,5 por ciento) y cocaína (51,6 por ciento). La elevada prevalencia de la patología dual y su repercusión asistencial hacen aconsejable disponer de programas terapéuticos especializados para su tratamiento.

Association in alcoholic patients between psychopathic traits and the additive effect of allelic forms of the CNR1 and FAAH endocannabinoid genes, and the 3' region of the DRD2 gene.

Little is known about the genetic factors that underlie the comorbidity between alcohol use disorder and antisocial personality disorder. Previous studies have associated both, dopaminergic and endocannabinoid systems to severe alcoholism with non-adaptive disrupted behaviours. In this work we have examined some gene variants involved in such systems in a sample of alcoholic patients to test whether there is a relationship with antisocial traits. The genetic analysis involved the genotyping of the single nucleotide polymorphism (SNP) TaqIA located nearby the DRD2 gene, the 10-repeat allele of a variable number tandem repeats (VNTR) of the SLC6A3 gene, the C385A FAAH SNP and the 3'-UTR microsatellite of CNR1 gene. The clinical study was performed in 137 Spanish alcohol dependent males. Antisocial Personality Disorder (DSM-IV) diagnosis was made by applying the International Personality Disorder Examination, and psychopathic traits were evaluated by the Hare's Psychopathy Checklist revised (PCL-R). The genotype distribution indicates there is a relationship between the TaqIA SNP, CNR1 and FAAH genes and PCL-R's Factor 1 in alcoholic patients. This relationship seems to be additive and independent and might be responsible for 11.4% of the variance in this PCL-R subscale. Our results suggest the implication of the dopaminergic and endocannabinoid systems in those processes leading to the comorbidity of alcoholism and antisocial behaviour.

From dopaminergic genes to psychiatric disorders.

Individual vulnerability to develop neurological and psychiatric disorders is associated with both genetic and environmental factors. Association studies in patients have explored the contribution of gene variants in the dopaminergic system in these disorders. This system is involved in motor control, endocrinological function, the reward system and cognition. The diverse physiological functions of dopamine are mediated by five different dopamine receptors, encoded by the genes DRD1, DRD2, DRD3, DRD4 and DRD5. These genes have various types of polymorphisms that can produce changes in the genetic product or expression levels. In recent years, the development of new technologies for genetic analysis, and a wider comprehension of the genetic sequences of these genes have increased our understanding of the implications of the dopaminergic system in both health and pathological states. It has also allowed the identification of genetic variants that may represent risk or protection factors for a variety of psychiatric disorders.

[COMT Val158Met polymorphism and schizophrenia in a series of Spanish patients]. / Polimorfismo Val158Met de COMT y esquizofrenia: estudio de asociación en una muestra de pacientes españoles.

BACKGROUND AND OBJECTIVE: Catecol-O-methyl transferase (COMT) enzyme plays a significant role in the regulation of the dopaminergic system in the prefrontal cortex. Several studies have assessed the association between modifications of the COMT activity and schizophrenia, but without consistent results. COMT gene contains a single nucleotide functional polymorphism which produces the change of a valine for a methionine at position 158. The effect of this aminoacid change is a modification of COMT enzymatic activity: valine-COMT displays a significantly higher capacity of postsynaptic dopamine degradation than methionine-COMT. The objective of this study is to carry out a genetic association study of the functional polymorphism Val158Met in a sample of Spanish schizophrenic patients and healthy controls. PATIENTS AND METHOD: This is a case-control study made up of 177 patients and 141 healthy controls. All patients -115 males and 62 females, with ages between 27 and 49 years; mean (standard deviation) of 38 (10.7) years- were being treated in the outpatient Psychiatric Clinic of the Hospital Universitario 12 de Octubre, and fulfilled the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria for schizophrenia (n = 162) or schizoaffective disorder (n = 15). Control subjects -92 males and 49 females, with ages between 26 and 47 years; mean of 36 (9.4) years- were free from medical and psychiatric disorders. Genotype identification was done by means of human genetic molecular techniques coupled to ADN polymerase chain reaction and single strand conformational polymorphism (SSCP) of the COMT Val158Met polymorphism. RESULTS: No statisticaly significant differences were found in the allele frequencies for this polymorphism between patient and control samples. Nevertheless, in genotype analysis and when a model of recessive inheritance (Val/Val vs Val/Met and Met/Met) was assumed, a possible tendency towards statistical significance was observed. Our results do not allow to confirm the possible COMT gene variants contribution to schizophrenia etiopathogenesis, but they offer some evidence which would point to its implication in some patients subgroups. CONCLUSIONS: With the results obtained in this study a possible contribution of the COMT gene in schizophrenia etiopathogenesis cannot be ruled out. The issue of the possible effect of the COMT Val158Met polymorphism in schizophrenia would remain to be open and calls for the need to replicate this kind of studies in greater samples that will allow stratificate analysis by patients subgroups.

Polimorfismo Val158Met de COMT y esquizofrenia: estudio de asociación en una muestra de pacientes españoles / COMT Val158Met polymorphism and schizophrenia in a series of Spanish patients

Fundamento y objetivo: La enzima catecol-O-metiltransferasa (COMT) interviene de un modo significativo en la regulación del sistema dopaminérgico, especialmente en la corteza prefrontal. Estudios previos han evaluado la asociación entre la actividad enzimática de la COMT y la esquizofrenia, aunque los resultados no han sido concluyentes. El gen COMT contiene un polimorfismo funcional que ocasiona, en la posición 158 del péptido, el cambio de valina por metionina y la modificación de la actividad enzimática, de forma que la COMT-valina muestra una capacidad de degradación postsináptica de la dopamina significativamente superior a la COMT-metionina. El objetivo de este trabajo es realizar un estudio de asociación genética con el polimorfismo funcional Val158Met del gen COMT en pacientes con esquizofrenia y en controles sanos españoles. Pacientes y método: Se ha realizado un estudio de casos y controles con una muestra de 177 pacientes y 141 controles. Los pacientes del estudio ­115 varones y 62 mujeres, con una edad entre 27 y 49 años; media (desviación estándar) de 38 (10,7) años­ se incluyeron consecutivamente según acudieron a las consultas del Servicio de Psiquiatría del Hospital Universitario 12 de Octubre y si cumplían criterios DSM-IV (cuarta edición del Diagnostic and Statistical Manual of Mental Disorders) para esquizofrenia (n = 162) o trastorno esquizoafectivo (n = 15). Asimismo, se incluyó a 141 controles evaluados, sanos y libres de enfermedad médica o psiquiátrica ­92 varones y 49 mujeres, con una edad entre 26 y 47 años, media de 36 (9,4) años­. La identificación del genotipo se llevó a cabo por medio de técnicas de genética molecular humana que asociaron la reacción en cadena de la polimerasa del ADN al estudio de la conformación de la hebra simple del ADN (single strand conformational polymorphism; SSCP) del polimorfismo Val158Met de COMT. Resultados: No se encontraron diferencias significativas en las frecuencias de los alelos para este polimorfismo al comparar controles y pacientes. Sin embargo, en el análisis por genotipos y desde un modelo de herencia recesivo (Val/Val frente a Val/Met y Met/Met), se detectó una posible tendencia a la significación. Nuestros resultados no permiten confirmar la posible contribución de variaciones del gen COMT en la etiopatogenia de la esquizofrenia, pero ofrecen indicios que permiten sospechar su participación en algunos grupos concretos de pacientes. Conclusiones: Con los resultados obtenidos en este estudio, la posible contribución del gen COMT en la etiopatogenia de la esquizofrenia no puede descartarse. El debate sobre el posible efecto del polimorfismo Val158Met de COMT en la esquizofrenia se mantendría abierto; de ahí la necesidad de reproducir los estudios en muestras mayores que permitan análisis estratificados de subgrupos de pacientes

Background and objective: Catecol-O-methyl transferase (COMT) enzyme plays a significant role in the regulation of the dopaminergic system in the prefrontal cortex. Several studies have assessed the association between modifications of the COMT activity and schizophrenia, but without consistent results. COMT gene contains a single nucleotide functional polymorphism which produces the change of a valine for a methionine at position 158. The effect of this aminoacid change is a modification of COMT enzymatic activity: valine-COMT displays a significantly higher capacity of postsynaptic dopamine degradation than methionine-COMT. The objective of this study is to carry out a genetic association study of the functional polymorphism Val158Met in a sample of Spanish schizophrenic patients and healthy controls. Patients and method: This is a case-control study made up of 177 patients and 141 healthy controls. All patients ­115 males and 62 females, with ages between 27 and 49 years; mean (standard deviation) of 38 (10.7) years­ were being treated in the outpatient Psychiatric Clinic of the Hospital Universitario 12 de Octubre, and fulfilled the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria for schizophrenia (n = 162) or schizoaffective disorder (n = 15). Control subjects ­92 males and 49 females, with ages between 26 and 47 years; mean of 36 (9.4) years­ were free from medical and psychiatric disorders. Genotype identification was done by means of human genetic molecular techniques coupled to ADN polymerase chain reaction and single strand conformational polymorphism (SSCP) of the COMT Val158Met polymorphism. Results: No statisticaly significant differences were found in the allele frequencies for this polymorphism between patient and control samples. Nevertheless, in genotype analysis and when a model of recessive inheritance (Val/Val vs Val/Met and Met/Met) was assumed, a possible tendency towards statistical significance was observed. Our results do not allow to confirm the possible COMT gene variants contribution to schizophrenia etiopathogenesis, but they offer some evidence which would point to its implication in some patients subgroups. Conclusions: With the results obtained in this study a possible contribution of the COMT gene in schizophrenia etiopathogenesis cannot be ruled out. The issue of the possible effect of the COMT Val158Met polymorphism in schizophrenia would remain to be open and calls for the need to replicate this kind of studies in greater samples that will allow stratificate analysis by patients subgroups

Anatomical and functional brain variables associated with clozapine response in treatment-resistant schizophrenia.

Clozapine alleviates the symptoms of a significant proportion of treatment-resistant schizophrenic patients. Previous studies suggest that the response to clozapine may be associated with prefrontal and temporal anatomy as well as with prefrontal, basal ganglia and thalamic metabolism. A sample of 25 treatment-resistant (TR) schizophrenic patients underwent magnetic resonance imaging (MRI) and 18F-deoxyglucose positron emission tomography (PET) before and after treatment with clozapine. We investigated the association between changes in positive, disorganized, and negative schizophrenic syndromes with clozapine treatment and a set of cerebral variables that included total intracranial volume (ICV); hippocampal, dorsolateral prefrontal (DLPF) and temporal gray-matter volume and metabolism; and metabolic activity of the thalamus, pallidum/putamen, and caudate head. Improvement in positive symptoms with clozapine was directly related to temporal gray-matter volume, whereas improvement of disorganization symptoms was inversely related to ICV and hippocampal volume. Patients with high baseline DLPF cortical volume and metabolic activity were more likely to experience improvement in their negative symptoms. We conclude that clinical improvement with clozapine may be related with the anatomy and metabolic activity of specific brain areas, with the structural integrity of the DLPF and temporal regions showing the maximum predictive capacity.

Multimodal neuroimaging studies and neurodevelopment and neurodegeneration hypotheses of schizophrenia.

The interpretation of the huge number of results in schizophrenia research using neuroimaging is uncertain. However, the simultaneous use of complimentary data obtained with these techniques may yield more relevant information in this regard. In this paper we present a series of studies performed by our group in two schizophrenic samples with the use of structural (magnetic resonance imaging, MRI), functional [glucose positron emission tomography (PET) and N-acetyl-aspartate (NAA) magnetic resonance spectrocopy] and neurophysiological techniques (the P300 event-related potential). Transversal and longitudinal measurements were performed.The integrated vision of the results so obtained allows us to propose the hypothesis of a neurodevelopmentally determined state of prefrontal disinihibition, in which the degree of atrophy would directly relate to the metabolic rate. This state would already be present in the first stages of illness and could have neurotoxic consequences in the long term. This would explain the findings of an association between sulcal cerebrospinal fluid (CSF) and illness duration and decreased NAA levels in chronic but not in recent-onset cases. The prefrotnal disinhibition would overstimulate the limbic system and the hippocampus would become overactivated, the metabolic rate at this level being inversely related to P300 amplitude. Clozapine showed a more selective and intense action on that hyperactive metabolic tone than haloperidol.