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OBJECTIVE: Despite the clinical observation that antipsychotics can produce negative symptoms, no previous controlled study, to our knowledge, has evaluated this action in healthy subjects. The present study assessed observer-rated and self-rated negative symptoms produced by conventional and second-generation antipsychotics in healthy volunteers. METHOD: The authors used a double-blind, placebo-controlled trial of single doses of haloperidol (5 mg) and risperidone (2.5 mg) in normal subjects. Thirty-two subjects were administered haloperidol, risperidone, and placebo in a random order. Motor variables and observer-rated negative symptoms were assessed after 3-4 hours and subjective negative symptoms and drowsiness after 24 hours. RESULTS: Neither of the active drugs caused significant motor extrapyramidal symptoms after administration. Haloperidol caused significantly more negative signs and symptoms than placebo on the Scale for the Assessment of Negative Symptoms (SANS) and two self-rated negative symptom scales: the Subjective Deficit Syndrome Scale total score and an analog scale that evaluates subjective negative symptoms. Risperidone caused significantly more negative signs and symptoms than placebo on the Brief Psychiatric Rating Scale (BPRS), the SANS, the Subjective Deficit Syndrome Scale total score, and the analog scale for subjective negative symptoms. After control for drowsiness, risperidone but not haloperidol produced more negative symptoms than placebo on the BPRS and the SANS. Significance was lost for the subjective negative symptoms with both drugs. CONCLUSIONS: Single doses of both haloperidol and risperidone produce negative symptoms in normal individuals. Drowsiness may be an important confounding factor in the assessment of negative symptoms in antipsychotic trials.

Introduction: Previous studies have associated a decreased striatal D2 dopamine receptor (DRD2) binding with impaired performance in cognitive tasks. In vivo studies have found a lower DRD2 binding associated with the CC genotype of the C957T single nucleotide polymorphism (SNP) of the DRD2 gene. Objective: The aim of this study was to investigate the relationship between executive functions and the C957T DRD2 SNP. We hypothesized that the CC genotype would be associated with a poorer executive functioning. Methods: Our sample consisted of 83 healthy volunteers (28 males and 55 females; mean age 25.2, SD 1.7 years). To assess executive functions, the Wisconsin Card Sorting Test was used, considering the variables perseverative errors, perseverative responses, and number of categories achieved. The genotype distribution was 13 CC, 41 CT, and29 TT, satisfying Hardy-Weinberg equilibrium. Results: Carriers of the CC genotype, compared with carriers of the CT/TT genotypes, achieved significantly fewer categories (5.00 vs. 5.81; p = 0.004), made a greater number of perseverative errors (13.46 vs. 8.39; p = 0.018), and had a greater number of perseverative responses (14.92 vs. 8.94; p = 0.014). Conclusions: Our results support the hypothesis that the C957T DRD2 SNP may influence cognitive performance through its repercussions on central dopaminergic function.

ResumenObjetivoSe ha reconocido una cantidad mayor de líquido cefalorraquídeo (LCR) cortical como un posible marcador de una pérdida de sustancia gris. Esta cantidad mayor en la esquizofrenia se encuentra predominantemente en las regiones prefrontal y temporal. Planteamos la hipótesis de que la evolución global y la respuesta al tratamiento peores en los varones con esquizofrenia se relacionan con una pérdida mayor de volumen cortical comparado con las mujeres.Sujetos y métodosPara comprobar esta hipótesis hemos utilizado imágenes de resonancia magnética (IRM) para estudiar los valores de LCR cortical (prefrontal, temporal y hemisférico) en un grupo de 85 pacientes con esquizofrenia, 56 de los cuales eran varones y 29, mujeres. Calculamos los valores residuales de LCR en los pacientes a partir de los datos relativos a 45 sujetos de control y regresión lineal, de los que se descontaron los efectos normales de la edad y el volumen intracraneal. Estas puntuaciones residuales constituyen una medida cuantitativa de la cantidad mayor de LCR debida a la enfermedad.ResultadosLos hombres, pero no las mujeres, presentaron una cantidad mayor significativa en el nivel de tendencia de LCR prefrontal izquierdo. Los valores residuales prefrontales y temporales se asociaban significativamente con la duración de la enfermedad en los varones, pero no en las mujeres.DiscusiónEstos resultados son compatibles con la peor evolución y la mayor gravedad de las anomalías estructurales encontradas por lo general en la esquizofrenia en los sujetos varones.ConclusionNuestros datos apoyan la hipótesis de una pérdida cortical prefrontal acelerada en los varones, pero no en las mujeres con esquizofrenia.

ObjectiveExcessive cortical cerebrospinal fluid (CSF) has been acknowledged as a possible marker of a gray matter loss. This excess in schizophrenia is found predominantly in the prefrontal and temporal regions. We hypothesized that the poorer global outcome and treatment response in males with schizophrenia are related to a greater cortical volume loss as compared to females.Subjects and methodsIn order to test this hypothesis we have used magnetic resonance imaging (MRI) to study the cortical (prefrontal, temporal, and hemispheric) CSF values in a group of 85 patients with schizophrenia, of whom 56 were males and 29, females. We calculated the residual values of CSF in the patients based on the data pertaining to 45 control subjects and linear regression, from which the normal effects of age and intracranial volume were discounted. These residual scores constitute a quantitative measurement of the excess of CSF due to the disease.ResultsMales, but not females, presented a trend-level significant excess of left prefrontal CSF. The prefrontal and temporal residual values were significantly associated with illness duration in males, but not in females.DiscussionThese results conform to the worse outcome and the higher severity of structural abnormalities generally found in schizophrenia in male subjects.ConclusionOur data support the hypothesis of accelerated prefrontal cortical loss in males, but not in females with schizophrenia.

Aims: To determine the clinically ascertained variables that are related to satisfactory response to naltrexone (NTX) treatment of alcohol dependence after detoxification. Methods: The use of intake and outcome variables were measured in a randomized 3-month open-controlled trial comparing the effects of naltrexone plus psychotherapy treatment versus psychotherapy treatment alone on the maintenance of abstinence in the final 28 days (n = 336, all male). Results: Predictors of a positive response to NTX treatment were family history of alcoholism (P = 0.010), early age at onset of drinking problems (P = 0.014) and comorbid use of other drugs of abuse (P < 0.001). Among the subjects not treated with NTX, the greater the number of predictor variables, the lower the final 28 days abstinence rates (P = 0.00003), but this was not the case in patients treated with NTX (P = 0.844). Conclusions: Patients with these features, suggesting biological vulnerability overall have poorer outcomes, but this can be reduced with NTX treatment. The type of alcoholism should be considered before deciding on the pharmacological strategy.

Over the past few years, advances in the investigation of the neurochemical circuits involved in the development and treatment of alcohol dependence have identified peptides and receptors as potential key targets in the treatment of problems related to alcohol consumption. The endogenous opioid system is modified by alcohol intake in areas of the brain related to reward systems, and differential basal levels of opioid gene expression are found in rodents with a high preference for ethanol. This suggests a greater vulnerability to alcohol consumption in relation to differences in genetic background. Further evidence of the involvement of opioid peptides in alcohol dependence is the ability of the opioid antagonist naltrexone to reduce alcohol intake in animal models of dependence and in alcohol-dependent patients. Abundant evidence indicates that the activation of cannabinoid receptors stimulates the release of opioid peptides, therefore the cannabinoid receptor antagonists may presumably alter opioid peptide release, thus facilitating the reduction of ethanol consumption. However, little is known about the effects of ethanol on the endogenous cannabinoid system, the vulnerability of cannabinoid receptors to alcohol intake or their neurochemical implications in reducing consumption of alcohol. In this paper, we review the role of opioid and cannabinoid receptor systems, their vulnerability to alcohol intake and the development of dependence, and the targeting of these systems in the treatment of alcoholism.

The study of cerebral variables associated with response to neuroleptics holds interest from both theoretical and clinical points of view. To date, no studies have aimed to identify predictors of response to olanzapine based on cerebral measurements. Here, we used magnetic resonance to assess the relationship between volumes of the prefrontal (dorsolateral and orbitofrontal) and temporal (temporal lobe and hippocampus) cortical regions and ventricles and, on the other hand, the response to olanzapine in 16 schizophrenic patients. Data from 42 healthy controls were used to calculate volume residuals in the patients, defined as deviations from the expected values, given individual age and intracranial volume. Residuals thus represent the effect of illness on regional measurements. The association between clinical change and those residuals was calculated separately for the positive, negative and total scores from the Positive and Negative Syndrome Scale (PANSS). There was a significant direct association between the degree of orbitofrontal atrophy and the improvement of positive symptoms with olanzapine. No predictors were found for change in the negative dimension. A trend was found for patients with larger ventricles to show a greater global decrease in total PANSS scores. Neither age nor duration of illness explained a significant proportion of the symptom improvement. This result, together with others from the literature, supports the idea that atypical antipsychotics may offer some benefit to patients with significant regional atrophy, and this may have implications for the choice of antipsychotic in clinical practice.

Aim: To specify the functional activity of cannabinoid CB 1 receptor in alcohol-preferring Fawn Hooded and alcohol nonpreferring Wistar rats under naive conditions. Method: Cannabinoid CB1 (WIN-55,212)-stimulated ( 35 S)-GTPs binding autoradiography, and cannabinoid CB 1 receptor gene expression were measured in rats of both strains that received only water. Results: Cannabinoid CB1 receptor stimulated ( 35 S)- GTPs binding was significantly lower in cingulate cortex (Cg), caudate-putamen (CPu), nucleus accumbens (Acc), ventromedial hypothalamic nucleus (VMN), amygdaloid area (AMG), fields (CA1, CA3) of the hippocampus and dentate gyrus (DG) in Fawn Hooded than in Wistar rats, whereas no differences were found either in substantia n igra pars reticulata (SNr) nor CA2 field of the hippocampus. In addition, cannabinoid CB 1 receptor gene expression was lower in Cg, CPu, VMN and CA3 field of the hippocampus in Fawn Hooded than in Wistar rats. Conclusions: We speculate that lower cannabinoid function appears to be related to greater vulnerability to alcohol consumption. Cannabinoid CB 1 receptor may represent a key target in the treatment of alcohol dependence.

Although a lower volume of prefrontal (PF) gray matter (GM) in patients with schizophrenia than in normal control subjects is a replicated finding, it is not yet clear whether this finding is present at the onset of illness. Clinical and imaging data suggest that the reduction in PF GM becomes apparent only some years following the onset of illness. To test this hypothesis, we used magnetic resonance imaging to study PF GM and sulcal cerebrospinal fluid (CSF) volumes in 81 schizophrenic patients. A Talairach-based tool was used for segmentation. Subjects included 44 healthy controls, 22 first-episode (FE), treatment-naïve patients with duration of illness of less than 1 year; 29 short-term chronic (SC) patients with durations of illness between 1.5 and 6 years; and 30 long-term chronic (LC) patients with duration of illness of more than 6 years. The data from healthy controls were used to calculate volume residuals in the patients, defined as deviations from the expected values given individual age and intracranial volume. The FE group did not show significant differences in GM or in CSF volumes compared with controls. However, both the SC and the LC patients showed the expected pattern of lower values for PF GM and an excess of PF sulcal CSF compared with controls. There were no significant differences between SC and LC patients in any of these measurements. There was a significant and inverse association between duration of illness and GM residuals. That association fit a nonlinear rather than a linear model, which was consistent with a decrease of GM volume during the first years following illness onset. No significant differences were found between those receiving atypical and typical antipsychotic drugs during the previous year.

This study aimed to examine the behavioural and neurochemical (cannabinoid CB1 receptor gene expression) changes induced by spontaneous cannabinoid withdrawal in mice. Tolerance was assessed by measuring rectal temperature and motor activity in the open-field test after CP-55, 940 administration. Cannabinoid withdrawal symptoms were determined by measuring motor activity and behavioural signs of abstinence. Cessation of CP-55, 940 treatment in tolerant mice induced a spontaneous time-dependent behavioural withdrawal syndrome consisting of marked increases (140%) in motor activity, number of rearings (170%), decreases in grooming (57%), wet dog shakes (73%) and rubbing behaviours (74%) on day 1, progressively reaching values similar to vehicle-treated mice on day 3. Interestingly, this spontaneous cannabinoid withdrawal resulted in CB1 gene expression upregulation (20–30%) in caudate-putamen, ventromedial hypothalamic nucleus, central amygdaloid nucleus and CA1, whereas in the CA3 field of hippocampus, a significant decrease (15–20%) was detected. Taken together, the results of this study suggest that cessation of CP-55, 940 administration in tolerant mice produces a behavioural cannabinoid withdrawal syndrome and a selective and differential responsiveness in CB1 receptor gene expression in several brain regions of the mice. These findings further suggest a time and regional differential role for cannabinoid receptors in short- and long-term neuroadaptations that occur after exposure to cannabis derivatives.

ResumenPropósito:La presencia del alelo Al del gen del receptor D2 de dopamina se ha asociado con predisposición al alcoholismo, aunque hay datos limitados sobre su expresión fenotípica en el alcoholismo.Objetivos:Determinar la importancia del alelo Al en las variables clínicas de la dependencia de alcohol.Metodología:Se estudió una muestra de 103 varones dependientes de alcohol. Se seleccionó a todos los pacientes consecutivamente del hospital general y entornos comunitarios. Los diagnósticos se hicieron con la Entrevista Clínica Estructurada para el DSM-III-R (SCID), y el Examen Internacional del Trastorno de la Personalidad (IPDE). El diagnóstico de alcoholismo familiar se hizo por entrevista directa o con los Criterios Diagnósticos para la Investigación-Historia Familiar (RDC-FH). Se utilizó el Índice de Gravedad de la Adicción (ASI) y la Escala de Gravedad de la Dependencia de Alcohol (SADS) para evaluar la gravedad de la dependencia del alcohol. La genotipación se hizo por los métodos de reacción en cadena de la polimerasa (RCP) y polimorfismos de longitud de fragmentos de restricción (PLFR).Resultados:El treinta y nueve por ciento aproximadamente de la muestra portaba el alelo Al (grupo A1+). Este grupo tenía prevalencias más altas de trastorno antisocial de la personalidad (60% frente a 15,9%) e historia familiar de alcoholismo (72,5% frente a 52,4%). Además, el grupo A1+ tenía un comienzo temprano del abuso de alcohol y más problemas con la bebida. La presencia de A1+ era el factor principal que explicaba el diagnóstico de trastorno antisocial de la personalidad, pero el peso de este factor no era suficiente para explicar las complicaciones evaluadas por el ASI.Conclusiones:Nuestros resultados apoyan la existencia de una asociación entre el alelo Al y factores derivados de la deficiencia dopaminérgica, denominada de otro modo síndrome de deficiencia de la recompensa.

Background: Anticonvulsant drugs have been used in the treatment of alcohol addiction with relatively good results. The purpose of the present study was to evaluate tolerance and safety of topiramate in patients presenting alcohol dependence. Methods: We studied 24 patients that fulfilled alcohol-dependence criteria (DSM-IV) and presented other psychiatric disorders for which the use of topiramate was indicated. During the 12 weeks of the study, the patients received topiramate (262 mg/ day) plus the psychoactive drugs they were taking for the other disorders. Carbohydrate-deficient transferrin (CDT) values and measures of craving and alcohol use were taken every 2 weeks. Results: Baseline rating of amount and frequency of craving and alcohol use decreased significantly by week 2, and CDT values decreased from week 6. Topiramate was well tolerated, and there were only three dropouts due to adverse events. Conclusion: Topiramate is safe and well tolerated, and may be beneficial in the treatment of alcohol dependence. A placebo-controlled study would be of interest.

Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for so-called genetic disorders, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in either knock-in or knock-out mice. However, there are similarly, many identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. Constituent cellular defense mechanisms responsive to the challenge of increased reactive oxygen species represent only one crossroad whereby environment can influence genetic predisposition. In this paper we highlight some of the major neurodegenerative disorders and discuss possible links of gene-environment interplay. The process of adult neurogenesis in brain is also presented as an additional element that influences gene-environment interplay. And the so-called priming processes (i.e., production of receptor supersensitization by repeated drug dosing), is introduced as yet another process that influences how genes and environment ultimately and co-dependently govern behavioral ontogeny and outcome. In studies attributing the influence of genetic alteration on behavioral phenotypy, it is essential to carefully control environmental influences.

In the last decade, a large number of studies using Delta9-tetrahydrocannabinol (THC), the main active principle derivative of the marijuana plant, or cannabinoid synthetic derivatives have substantially contributed to advance the understanding of the pharmacology and neurobiological mechanisms produced by cannabinoid receptor activation. Cannabis has been historically used to relieve some of the symptoms associated with central nervous system disorders. Nowadays, there are anecdotal evidences for the use of cannabis in many patients suffering from multiple sclerosis or chronic pain. Following the historical reports of the use of cannabis for medicinal purposes, recent research has highlighted the potential of cannabinoids to treat a wide variety of clinical disorders. Some of these disorders that are being investigated are pain, motor dysfunctions or psychiatric illness. On the other hand, cannabis abuse has been related to several psychiatric disorders such as dependence, anxiety, depression, cognitive impairment, and psychosis. Considering that cannabis or cannabinoid pharmaceutical preparations may no longer be exclusively recreational drugs but may also present potential therapeutic uses, it has become of great interest to analyze the neurobiological and behavioral consequences of their administration. This review attempts to link current understanding of the basic neurobiology of the endocannabinoid system to novel opportunities for therapeutic intervention and its effects on the central nervous system.

A multitude of factors, that either singly, interactively, or sequentially influence the gene-environment interplay in affective and dementia states, include several phases of neurodevelopmental liability in both humans and laboratory animals. Genetic vulnerability for both affective disorders and dementia describes a scenario distinguished by progressive need for concern, particularly in view of the interplay between these areas of ill-health. The contribution of emotional and cognitive expression to personal outcomes, e.g., as a function of affective personality type, a state-dependent analysis of personality characteristics, appears to pervade both the individual's experience of social and physical environments and the performance of cognitive tasks. The role of the endocannabinoids in mental health may offer insights for the psychopharmacology of both cognition and affect. Maladaptive emotional reactions and a defective cognitive ability will contribution to unsatisfactory/maladaptive coping strategies, in turn, leading to further complications of an affective and dysfunctional nature, eventually with a clinical psychopathological outcome. These considerations impinge upon critical issues concerning predisposition and vulnerability. Classical eye-blink conditioning provides a highly established procedure for assessment of defective physiology in models of Alzheimer's dementia. In order to develop a consideration of the array of situations presenting the variation of outcome due to type of affective personality, the role of fear and anxiety and stress in affective states influencing cognition are examined and the critical role of brain circuits mediating emotions influencing cognitive outcomes is discussed.

The TaqIA1 allele of the dopamine receptor gene D2 (DRD2) has been associated with alcoholism, as well as with other addictive behaviours. The exact nature of how the presence of this allele can be a vulnerability factor in the development of alcoholism remains unclear. In this study we found that the presence in the DRD2 genotype of the TaqIA1 allele in Spanish alcoholics is associated with higher levels of urine homovanillic acid (HVA) when compared to patients homozygous for the TaqIA2 allele. A sample of 142 Spanish male alcoholic patients was split into 2 groups on the basis of the presence or absence of the A1 allele in their genotype. The urine sample was analyzed by high performance liquid cromatography (HPLC), and the concentration of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and vanilylmandelic acid (VMA) was determined. We found a statistical difference in the concentration of HVA between the groups, that suggests this polymorphism could be related to the variance of urine HVA levels.

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.

Background. –Presence of A1 allele of the DRD2 gene has been associated with a predisposition for alcoholism although there are limited data about its phenotypic expression in alcoholism.Objectives. –To determine the importance of the A1 allele in clinical variables of alcohol dependence.Methodology. –A sample of 103 alcohol-dependent males was studied. All patients were recruited consecutively from the general hospital and community settings. The diagnostics were made with the structured clinical interview for DSM-III-R (SCID); and the International Personality Disorder Examination (IPDE). Diagnosis of family alcoholism was made by direct interview or with the Research Diagnostic Criteria-Family History (RDC-FH). The Addiction Severity Index (ASI) and the Severity of Alcohol Dependence Scale (SADS) were used to assess alcohol dependence severity. Genotyping was done by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods.Results. –Approximately 39% of the sample carried the A1 allele (A1+ group). This group had higher prevalences of antisocial personality disorder (60% vs. 15.9%); and alcoholism family history (72.5% vs. 52.4%). Also A1+ had early onset alcohol abuse and more drinking problems. The presence of A1+ was the main factor to explain the diagnosis of antisocial personality disorder, but the weight of this factor was not sufficient to explain the complications assessed by the ASI.Conclusions. –Our results support the existence of an association between the A1 allele and factors resulting from dopaminergic deficiency, otherwise denominated reward deficiency syndrome.

This study examined behavioural signs that occur during tolerance development to cannabinoid treatment and hormonal and gene expression alterations induced by spontaneous cannabinoid withdrawal in mice. Tolerance to CP-55,940 treatment developed for hypothermia, ambulatory and exploratory locomotor activity. Cessation of cannabinoid treatment resulted in a behavioural withdrawal syndrome characterized by a pronounced increase in ambulatory activity and rearings. Corticosterone plasma concentrations dramatically increased 24 and 72 h after cessation of cannabinoid treatment. Similarly, an increase (40%) in cannabinoid [35S]GTPgammaS binding autoradiography was detected on days 1 and 3 of abstinence. Spontaneous cannabinoid withdrawal produced time-related significant alterations in gene transcription: (i) decreased (20%) tyrosine hydroxylase (TH) mRNA levels in the ventral tegmental area and increased (50%) in substantia nigra; (ii) increased proenkephalin (PENK) gene expression more than 100% in caudate-putamen, nucleus accumbens, olfactory tubercle and piriform cortex; (iii) increased (20-40%) pro-opiomelanocortin (POMC) gene expression in the arcuate nucleus of the hypothalamus. These results suggest that spontaneous cannabinoid withdrawal occur after cessation of CP-55,940 treatment. This 'syndrome' includes behavioural, hormonal and gene transcription alterations that seems to be part of the regulation of neuronal plasticity induced by spontaneous cannabinoid withdrawal.

This paper compares the metabolic changes associated with risperidone treatment in schizophrenia to those induced by haloperidol, as a representative typical neuroleptic. A group of 11 schizophrenic patients of recent onset underwent two [ 18 F] fluoro-desoxi-glucose (FDG)-positron emission tomography (PET) scans at rest: the first one at the moment of the diagnosis, after a minimal treatment with haloperidol followed by wash-out, and the second one after 6 months on risperidone. The study also included 34 patients on chronic haloperidol for comparison. PET images were analyzed using Statistical Parametric Mapping (SPM′99) methods. The only change after treatment with risperidone with respect to the baseline was a slight increase in activity in the primary visual area and the right insula. Patients on chronic haloperidol showed increased activity in the motor cortex and cerebellum, as compared to both minimally treated and risperidone-treated patients. The pattern of metabolic changes induced by risperidone appears to be different from that produced by typical antipsychotics.

Resumen Objetivo En el abordaje de los trastornos por uso de alcohol se utilizan diversas psicoterapias como coadyuvantes del tratamiento psicofarmacologico. Material y metodos Se revisan las intervenciones psicosociales utilizadas en el tratamiento del alcoholismo. Resultados A continuacion vamos a exponer las descritas en la literatura, el fundamento teorico, procedimiento y eficacia de cada una de ellas, haciendo mas hincapie en las de mayor utilizacion por los profesionales que manejan el alcoholismo. Conclusiones Se agrupan en terapias cognitivoconductuales (prevencion de recaidas, tecnicas de autocontrol, entrenamiento en habilidades sociales, desensibilizacion sistematica), terapias conductuales (terapia aversiva, contrato de contingencias, exposicion con prevencion de respuesta) y terapias psicodinamicas. Asimismo, se mencionan la intervencion familiar y grupal.

Naltrexone is widely used in therapeutic programs with abstinence as a goal. However, it has been used in only a few studies aimed at reducing alcohol consumption. The purpose of this study was to evaluate the efficacy of naltrexone as an adjunct in controlled drinking programs. This was an open randomized study of 12 weeks duration that compared two therapeutic strategies: use of naltrexone in a controlled drinking program (NTX+CD) and the controlled drinking program alone (CD), without NTX. Each group comprised 30 male patients with mild alcohol dependence. During treatment, there were no differences between groups in drinking behavior, though the NTX+CD group showed significantly less craving. In the 12-month follow-up period, the NTX+CD group showed significantly fewer drinking days and heavy drinking days and less craving than the CD group. The results of this study suggest a role for naltrexone in controlled drinking programs.

Changes in sulcal cerebrospinal fluid (CSF) volume have been related to the neurodegeneration hypothesis in schizophrenia. Fifty-three (24 neuroleptic-naive) schizophrenics and a control group (n=26) were studied with MRI to assess regional sulcal CSF values relative to the total volume of brain lobes (prefrontal, orbital, temporal, parietal, and occipital). Segmentation of brain structures was performed using an automatic Talairach-based method. Relative CSF volumes were adjusted for age by means of linear regression from normal subjects; the corrected values were used to assess their relationship with illness duration and age of onset (AOS). The volume of sulcal CSF on prefrontal and temporal lobes (bilateral) was significantly greater in schizophrenic patients and showed a significant positive correlation with illness duration not found in the other regions studied. No significant association between CSF volumes and AOS was found in any region. Our findings support the existence of a degenerative process in schizophrenia located in prefrontal and temporal areas.

Five experiments were performed to assess the changes in motor activity resulting from neonatal administration of 6-hydroxydopamine (6-OHDA) on Days 1 or 2 postnatal, at doses of either 75 or 100 micro g in a volume of 10 micro l vehicle, following pretreatment with either GBR 12909 (40 mg/kg, s.c.) or amphonelic acid (4.0 mg/kg, s.c.) or saline. Motor activity was measured either over 60-min test periods on five consecutive days of testing or at 12-min intervals within a single 60-min test session. The initial extent of locomotor hyperactivity was dependent upon the neonatal dose of 6-OHDA: the 100 micro g, but not 75 micro g, dose induced marked hyperactivity from test day 1 onwards whereas the 75 micro g dose did so from test day 3 onwards. The initial hypoactivity for rearing behaviour was observed for both doses of 6-OHDA: this hypoactivity was altered over successive test days so that by test day 5 an hyperactivity by the 75 micro g, but not 100 micro g, was observed. Pretreatment with either GBR 12909 or amphonelic acid abolished the effects of both doses of 6-OHDA. In the within-60-min test session procedure, 6-OHDA treated rats (both 75 and 100 micro g) showed initial hyperactivity for locomotion that intensified, in relation to the other groups, over each 12-min interval and initial hypoactivity for rearing that developed into hyperactivity over each 12-min interval. Pretreatment with either GBR 12909 or amphonelic acid again abolished the effects of both doses of 6-OHDA. Habituation quotients derived in each case for both procedures indicated severe habituation deficits by 6-OHDA (75 and 100 micro g) rats, compared to the control groups in all four experiments. In Experiment V, a low dose of D-amphetamine abolished the hyperactivity of 6-OHDA (75 micro g) treated rats whereas a higher dose did so only transiently. Pretreatment with GBR 12909 abolished these effects. These findings underline the neuropharmacological utility of the neonatal 6-OHDA treatment for studying brain receptor system adaptive changes underlying the respective functional alterations and as a possible laboratory model for clinical disorders.

Background and Objectives: A relationship has been found between cognition and functioning in patients with schizophrenia. Our objective was to study the relationship between the cognitive domains assessed by the MATRICS Consensus Cognitive Battery (MCCB), and functioning as evaluated using the functioning subscale of the Global Assessment of Functioning scale (GAF-f). Methods: A sample of 83 clinically stable outpatients diagnosed with schizophrenia according to DSM-IV criteria were assessed using the MCCB and the GAF-f. Pearson correlations and stepwise linear regression analyses were performed. Results: Correlation analysis between the GAF-f and the cognitive domains of the MCCB showed a significant relationship between functioning and all of the cognitive domains. Regression yielded a statistically significant model (F2,74 = 20.4, p < 0.001) in which functioning was related to Speed of processing (standardized β = 0.369, p = 0.001) and to Social cognition (standardized β = 0.325, p = 0.003). Together, these two variables explained 33.8% of the variance of functioning. Conclusions: Both speed of processing and social cognition have an important association with functioning in patients with schizophrenia.

Genome wide association studies (GWAS) has allowed the discovery of some interesting risk variants for schizophrenia (SCZ). However, this high-throughput approach presents some limitations, being the most important the necessity of highly restrictive statistical corrections as well as the loss of statistical power inherent to the use of a Single Nucleotide Polymorphism (SNP) analysis approach. These problems can be partially solved through the use of a polygenic approach. We performed a genotyping study in SCZ using 86 previously associated SNPs identified by GWAS of SCZ, bipolar disorder (BPD) and autistic spectrum disorder (ASD) patients. The sample consisted of 3063 independent cases with DSM-IV-TR diagnosis of SCZ and 2847 independent controls of European origin from Spain. A polygenic score analysis was also used to test the overall effect on the SCZ status. One SNP, rs12290811, located in the ODZ4 gene reached statistical significance (p = 1.7 x 10(-4), Allelic odds ratio = 1.21), a value very near to those reported in previous GWAS of BPD patients. In addition, 4 SNPs were close to the significant threshold: rs3850333, in the NRXN1 gene; rs6932590, at MHC; rs2314398, located in an intergenic region on chromosome 2; and rs1006737, in the CACNA1C gene. We also found that 74% of the studied SNPs showed the same tendency (risk or protection alleles) previously reported in the original GWAS (p < 0.001). Our data strengthen the polygenic component of susceptibility to SCZ. Our findings show ODZ4 as a risk gene for SCZ, emphasizing the existence of common vulnerability in psychosis. (C) 2014 Published by Elsevier B. V.

The number of large collaborative research networks in mental health is increasing. Training programs are an essential part of them. We critically review the specific implementation of a research training program in a translational Centre for Biomedical Research in Mental Health in order to inform the strategic integration of basic research into clinical practice to have a positive impact in the mental health system and society. Description of training activities, specific educational programs developed by the research network, and challenges on its implementation are examined. The Centre for Biomedical Research in Mental Health has focused on training through different activities which have led to the development of an interuniversity master's degree postgraduate program in mental health research, certified by the National Spanish Agency for Quality Evaluation and Accreditation. Consolidation of training programs within the Centre for Biomedical Research in Mental Health has considerably advanced the training of researchers to meet competency standards on research. The master's degree constitutes a unique opportunity to accomplish neuroscience and mental health research career-building within the official framework of university programs in Spain.

The purpose of this study was to examine the time course effects of extinction of cocaine self-administration behavior on proenkephalin (PENK) gene expression in caudate-putamen nucleus (ST), nucleus accumbens (Acc), olfactory tubercle (Tu), piriform cortex (Pir), ventromedial hypothalamic nucleus (VMN), and central amygdala (Ce) as measured by in situ hybridization histochemistry. Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (1) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT); (2) noncontingent injections of either 1 mg/kg/injection of cocaine (NONCONT); or (3) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a FR5 schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (day 0) and 1-, 5-, and 10-day after the second extinction period, animal brains in each triad were removed to be processed for in situ hybridization. PENK mRNA levels were significantly higher in the cocaine groups when compared with SALINE group in the ST, Acc, Pir, and Tu regions on days 0, 1, 5, and 10 of the extinction and lower in the Ce region of CONT group when compared to NONCONT and SALINE groups on days 1, 5, and 10 of the extinction period. In the VMN nucleus, PENK mRNA content in CONT group versus NONCONT and SALINE groups was also lower, but there were statistically significant differences only on day 5. These results suggest that changes in PENK gene expression after contingent cocaine administration might be involved in cocaine withdrawal states.

Mechanisms of neuronal cell death in apoptosis and necrosis are examined. Neurotoxic processes underlying cellular destruction may involve N-methyl-D-aspartate (NMDA) receptor activation and/or activation of neuronal nitric oxide synthase but the depletion of energy and generation of free radicals appears to be critical. In Alzheimer's disease the damaging effects of peroxynitrite and exposure to beta-amyloid peptide is evident. Mitochondrial dysfunction is involved in several neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease as well as Alzheimer's disease and in these disorders the innovations offered by techniques ranging from transgenic mouse models of the disorder to cell culture preparations are remarkable. Agents of neuroprotection and neurorestoration possess either characteristics specific to particular disorders or have a general applicability or both. The vast array of agents available are for the most part the objectives of laboratory examinations but an increasing selection of compounds are reaching the clinical necessities thereby influencing current strategic notions to modify tactical contingencies. Among the agents listed are included: inhibitors of the enzyme poly-ADP-ribose polymerase, inhibition of apoptotic cell death, agents acting on mitochondrial permeability transition, excitatory amino acid antagonists, applications of neurotrophins, immunophilins, agents influencing heme oxygenase-1 expression and iron sequestration in aging astroglia, improvements in mitochondrial energy production or buffering, and finally dopaminemimetics with differential affinities for dopamine receptors.

Los pacientes con dependencia alcoholica de larga evolucion frecuentemente presentan sintomas depresivos durante las primeras semanas tras la desintoxicacion. Aunque se ha descrito que en la mayoria de los casos esta clinica depresiva suele mejorar espontaneamente tras 4-6 semanas de abstinencia, frecuentemente requieren tratamiento antidepresivo. En ocasiones, incluso a pesar de haberse instaurado un tratamiento antidepresivo convencional, persiste parte de los sintomas depresivos. Estos sintomas depresivos persistentes, desde un punto de vista neurobiologico, podrian tener relacion con la disfuncion hipodopaminergica descrita tras cesar el consumo enolico. Presentamos el caso de un varon de 49 anos, con dependencia alcoholica de larga evolucion, que presentaba sintomas depresivos resistentes al tratamiento antidepresivo convencional tras haber superado el periodo inicial de desintoxicacion. El paciente mostro una mejoria de los sintomas depresivos persistentes despues de anadir amisulprida, a dosis de 100 mg/dia, a su tratamiento antidepresivo.

The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta- analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non- SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. Schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis.. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD.

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 KliniskeUndersogelser (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-naive patients with schizophrenia, and this can be explained for the most part by greater adherence to this treatment.

Cognitive deficits constitute a core symptom in schizophrenia, are difficult to treat, and have special relevance regarding prognosis and functional outcome. The search for pharmacological strategies for improving cognition in schizophrenic patients has been hindered by the lack of a consensus regarding instruments for cognitive assessment. The 'Measurement and Treatment Research to Improve Cognition in Schizophrenia' (MATRICS) initiative of the U.S. National Institute of Mental Health (NIMH) set the development of a consensus cognitive battery as one of its objectives. In a first phase, the seven cognitive domains which have been shown to be impaired in schizophrenia and that were to be assessed were identified: Speed of processing, Attention/Vigilance, Working memory, Verbal learning, Visual learning, Reasoning and problem solving, and Social cognition. In a second phase, the MATRICS Consensus Cognitive Battery (MCCB) was developed. This is a cognitive assessment battery composed of ten instruments, which assess the seven domains in a little over one hour. The MCCB has been standardized in U.S. population, and the Spanish standardization has been recently published.

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 Cronbach's 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). Cronbach's 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.

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.

Specific cannabinoid receptors have been recently described in extrapyramidal and limbic areas and presumably might mediate the effects of marijuana exposure on behavioral processes related to those areas. In this work, we examined whether cannabinoid receptors exhibit downregulation as a consequence of the chronic exposure to Δ 9 -tetrahydrocannabinol (THC), which might explain certain tolerance phenomena observed in relation to motor and limbic effects of marijuana. To this end, we first characterized the binding of cannabinoid receptors, by using [ 3 H]CP-55,940 binding assays, in the striatum, limbic forebrain, and ventral mesencephalon of male rats, and, second, we measured the density and affinity of those receptors in these brain areas after 7 days of a daily treatment with THC. Development of a tolerance phenomenon was behaviorally tested by using an open-field technique. Results were as follows. The three areas studies presented specific and saturable binding for the cannabinoid ligand, as revealed by their corresponding association and dissociation curves, displacement by THC, saturation curves, and Scatchard plots. A chronic treatment with THC produced the expected tolerance phenomenon: The decrease caused by an dose in spontaneous locomotor (49.4%) and exploratory (59.7%) activities and, mainly, the increase in the time spent by the rat in inactivity (181.7%) were diminished after 7 days of daily treatment (39.4, 40.4, and 31.7%, respectively). This tolerance was accompanied by significant decreases in the density of cannabinoid receptors in the striatum and limbic forebrain, the areas where nerve terminals for nigrostriatal and mesolimbic dopaminergic systems, respectively, which play an important role in those processes, are located. This downregulation phenomenon was also observed in the ventral mesencephalon, the area where cell bodies for both dopaminergic neuronal systems are clustered, but the decrease was smaller and nonsignificant. No modifications were seen in the affinity of these receptors by chronic exposure to THC. In summary, a chronic treatment with THC produced downregulation of cannabinoid receptors in the striatum and limbic forebrain and a nonsignificant trend in the ventral mesencephalon. This observation might explain the tolerance phenomena observed in the effects of THC on motor and limbic behaviors after chronic exposures.

The maintenance of self-reported quality of life (QL) among people on the liver transplantation waiting list is one of the priority objectives of transplantation teams. Although there are different determinant factors of QL, results are not conclusive. In our study, the goal was to evaluate both the influence of cirrhosis etiology (ethylic and non-ethylic) and the coping strategies used concerning QL. A sample of 93 patients was selected, divided into two groups: ethylic cirrhosis (EC) and non-ethylic cirrhosis (NEC). QL was evaluated through the SF-36 Health Survey, and coping strategies through the Medical Coping Modes Questionnaire (MCMQ). Our results indicated that subjects with EC obtained similar QL levels to subjects with NEC, on all the SF-36 and MCMQ subscales. Furthermore, negative correlations were found between avoidance and acceptance-resignation coping strategies with the SF-36 components. Consequently, the acceptance-resignation strategy was associated with a worse perception of physical functioning, general and mental health, and vitality and role-emotional. Overall, these results suggest that cirrhosis etiology is not a determinant factor of QL, whereas the acceptance-resignation coping strategy might lead to lower self-perception of QL.

The TaqIA single-nucleotide polymorphism (SNP), which is the most widely studied genetic polymorphism in addictions, is located at the gene that encodes the RIP kinase ANKK1 near the gene for dopamine receptor D2. The TaqIA SNP is in strong linkage disequilibrium with the SNP rs7118900, which changes the alanine at position 239 to threonine in the ANKK1 protein (Ala239/A2; Thr239/A1). In silico analysis has predicted that this polymorphic substitution creates an additional phosphorylation site in the kinase domain of ANKK1. To investigate the contribution of ANKK1 to the pathophysiology of TaqIA-associated phenotypes, we analyzed transfected HEK293T cells with the human ANKK1-kinase(Ala239) and ANKK1-kinase(Thr239) variants tagged with GFP. We observed that the ANKK1-kinase is located in both the nucleus and the cytoplasm, suggesting that there is nucleocytoplasmic shuttling of this putative signal transducer. In addition, we found that the Ala239Thr ANKK1-kinase polymorphism exhibited strong expression differences in both the nucleus and the cytoplasm at basal level and when stimulated with the dopamine agonist apomorphine. Specifically, the ANKK1-kinase(Thr239) variant showed the highest level of basal protein expression, while ANKK1-kinase(Ala239) was 0.64-fold lower. After treatment with apomorphine, ANKK1-kinase(Ala239) showed a 2.4-fold increment in protein levels, whereas a 0.67-fold reduction was observed in ANKK1-kinase(Thr239). Thus, here we provide the first evidence of functional ANKK1 differences that are marked by TaqIA and could be associated with vulnerability to addiction.

Dopaminergic dysfunction in the prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. In the PFC, dopamine signalling largely depends on the D1 receptors, which are coded by the DRD1 gene, and on the regulation of dopamine levels by the enzyme catechol-O-methyltransferase (COMT). Here, we investigate the role of DRD1 and its interaction with the COMT gene in schizophrenic patients. In two gender-limited independent patient and control samples, we genotype five Tag single nucleotide polymorphisms (tagSNPs) of DRD1. The DRD1 SNP and haplotype associations, as well as interaction effects with the Val158Met COMT SNP were analyzed. In the male sample, we found the rs11746641 and rs11749676 DRD1 SNPs were associated with schizophrenia. Haplotype analyses identified the T-A-T-C-T variant related to a protective effect (P = 0.008) and the G-G-T-C-C variant that showed a tendency to be a risk factor for the disorder (P = 0.012). A logistic regression analysis revealed a significant pattern of interaction between DRD1 and COMT for both the rs11746641 (P = 0.002) and rs11749676 (P = 4.5 x 10(-5)) SNPs. DRD1-associated haplotypes were exclusively related to schizophrenia in the Val homozygous subgroup of patients (T-A-T-C-T: P = 0.003; G-G-T-C-C: P = 0.006). In females, none of the DRD1 SNPs were linked to the disorder. Our genetic data suggest that DRD1 and COMT are epistatically associated with protection against and the risk of developing schizophrenia in a gender-dependent fashion, and support the role of dopamine dysfunction at the PFC in the pathophysiology of this disorder.

Tardive dyskinesia (TD) is a severe and potential irreversible side effect of antipsychotic treatment. Treatment of established TD is often unsuccessful. In this article, we report three cases of psychogeriatric patients who suffered from TD as a side effect of long-term treatment with haloperidol that resolved after switching treatment to aripiprazole. Potential psychopharmacological mechanisms explaining this finding are briefly discussed.

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. © 2009 Elsevier B.V. All rights reserved.

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. © 2009 Wiley-Liss, Inc.

The contributions of impulsive and risk-taking behaviour in depressive and bipolar disorders, motivational and motor behaviours in anhedonic and substance addictive states, and the factors, particularly distress and trauma, underlying the development of neuropathology in affective status are described from clinical, epidemiological and laboratory perspectives. In order to distinguish one case factor for biopsychological substrates of health, an array of self-reported characteristics, e.g., positive or negative affect, stress or energy, optimism, etc., that may be predictive or counterpredictive for the propensity for physical exercise and activity were analysed using a linear regression in twelve different studies. Several individual characteristics were found to be markedly and significantly predictive of the exercise propensity, i.e., positive affect, energy, health-seeking behaviour and character, while optimism was of lesser, though significant, importance. Several individual characteristics were found to be significantly counterpredictive: expression of BDI- and HAD-depression, major sleep problems and lack/negligence of health-seeking behaviour. The consequences of physical activity and exercise for both affective well-being, cognitive mobility and neurogenesis is noted, particularly with regard to developmental assets for younger individuals. Affective disorder states may be studied through analyses of personal characteristics that unfold predispositions for symptoms-profiles and biomarkers derived from properties of dysfunction, such as impulsiveness, temperament dimensions, anhedonia and 'over-sensitivity', whether interpersonal or to reward.

Symptoms and syndromes in neuropathology, whether expressed in conscious or nonconscious behaviour, remain imbedded in often complex diagnostic categories. Symptom-based strategies for studying brain disease states are driven by assessments of presenting symptoms, signs, assay results, neuroimages and biomarkers. In the present account, symptom-based strategies are contrasted with existing diagnostic classifications. Topics include brain areas and regional circuitry underlying decision-making and impulsiveness, and motor and learned expressions of explicit and implicit processes. In three self-report studies on young adult and adolescent healthy individuals, it was observed that linear regression analyses between positive and negative affect, self-esteem, four different types of situational motivation: intrinsic, identified regulation, extrinsic regulation and amotivation, and impulsiveness predicted significant associations between impulsiveness with negative affect and lack of motivation (i.e., amotivation) and internal locus of control, on the one hand, and non-impulsiveness with positive affect, self-esteem, and high motivation (i.e., intrinsic motivation and identified regulation), on the other. Although presymptomatic, these cognitive-affective characterizations illustrate individuals' choice behaviour in appraisals of situations, events and proclivities essentially of distal perspective. Neuropathological expressions provide the proximal realities of symptoms and syndromes with underlying dysfunctionality of brain regions, circuits and molecular mechanisms.

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.

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.

BackgroundThe Taql-A polymorphism of the ANKK1 gene, adjacent to the DRD2 gene, has been associated with alcoholism and other psychiatric conditions, although other DRD2 gene variants, such as the C957T polymorphism, could be related to these phenotypic traits.AimsTo investigate the contribution of the Taql-A and the C957T polymorphisms to the presence of psychopathic traits in patients with alcoholism.MethodWe performed association and interaction analyses of the polymorphisms in 150 controls and 176 male alcohol-dependent patients assessed for the presence of dissocial personal disorder, using the Psychopathy Checklist-Revised (PCL-R).ResultsThere was a significant association of the Taql-A and C957T polymorphisms when both genotypes were present, with PCL-R scores of F1–171=0.13 (P=0.01) and a frequency of dissocial personal disorder OR=10.52, PConclusionsThe Taql-A of the ANKK1 gene and the C957T of the DRD2 gene are epistatically associated with psychopathic traits in alcohol-dependent patients.

Objective: The development of alcohol dependence is associated with specific individual personality traits and previous consumption of other drugs of abuse. However, there is little information on these risk factors in heavy drinkers before and after they meet the criteria for alcohol dependence. This study examined the influence of cocaine use and the role of impulsivity in the development of DSM-IV alcohol dependence in nondependent drinkers in a 4-year follow-up study. Method: A prospective cohort study was conducted to establish the risk factors associated with DSM-IV alcohol dependence. Four hundred seventy-one (nondependent) heavy drinkers were enrolled in a prospective study. At baseline, 280 were classified as heavy drinkers (HD) and 191 as heavy drinkers who also used cocaine (HD + Co). Clinical variables related to alcohol and cocaine use were assessed at 2 years and at the end of the 4-year follow-up period. The study was conducted from September 2001 until September 2006 in Madrid, Spain. Results: At the 4-year follow-up assessment, 67.9% of the HD + Co group met DSM-IV criteria for alcohol dependence compared to 13.6% of the HD group. Odds ratios for alcohol dependence were 12.3 and 7.0 for male and female cocaine users, respectively. Clinical and psychological variables related to impulsivity were associated with the development of alcohol dependence. The amount of cocaine used during follow-up was associated with a more rapid progression to alcohol dependence. Conclusions: This study revealed that cocaine use or an impulsive personality in heavy drinkers increased the risk of developing DSM-IV alcohol dependence by 3.8 and 12.6 times, respectively. These results may be useful in designing new strategies for preventing the development of alcohol dependence.

Background: Although many studies have established a close relation between impulsivity and alcohol use disorders, little is known about the role of behavioral impulsivity in the development of these disorders. Objectives: To determine the role of 2 laboratory paradigms of impulsivity in the development of alcohol use disorders. Methods: Follow-up study carried out with 471 participants diagnosed as heavy drinkers (HD) and followed-up for 4 years. Initially, they were compared with a healthy control group. Assessment of behavioral impulsivity was carried out with the Continuous Performance Test (CPT), and the Stop-Signal Task (SST) assessed behavioral inhibitory control. Differential reinforcement for low-rate responding (DRLR) was used to evaluate the delay reward dimension. The Structured Clinical Interview (SCID-DSM-IV) was used to diagnose alcohol dependence. Results: The HD performed worse than the control group in all the behavioral tests of impulsivity. Performance in DRLR was the only behavioral impulsivity test that classified the HD correctly compared to controls. Logistic regression analysis indicated that performance on SST was a significant predictor [odds = 1.52(CI = 1.08–2.31)] of developing alcohol dependence. Conclusions: Our results support the relation between behavioral impulsivity and alcohol use disorders. The paradigm related to delay of reward may be a factor associated with the use of alcohol and the incapacity to control inhibition as dependence develops.