Gabriel Rubio

The role of behavioral impulsivity in the development of alcohol dependence: a 4-year follow-up study.

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.

Long-Acting Injectable Risperidone Compared with Zuclopenthixol in the Treatment of Schizophrenia with Substance Abuse Comorbidity

Objective: This study aimed to compare the efficacy of long-acting risperidone and zuclopenthixol in subjects with schizophrenia and substance abuse. Method: A total of 115 subjects with schizophrenia and substance use disorders were enrolled for an open, randomized, controlled, 6-month follow-up study. Fifty-seven subjects were selected for treatment with long-acting injectable risperidone, while another 58 were treated with zuclopenthixol-depot. Results: Long-acting risperidone patients presented fewer positive urine tests (8.67 compared with 10.36, P = 0.005), showed improved scores on the Positive and Negative Syndrome Scale, and showed better compliance with the Substance Abuse Management program. The use of long-acting risperidone and less severe dependence explained the outcome at the end of the follow-up. Conclusions: Long-acting injectable risperidone was more effective than zuclopenthixol-depot in improving substance abuse and schizophrenia symptoms in subjects with dual diagnosis.

Hypofunction of Right Temporoparietal Cortex During Emotional Arousal in Depression

CONTEXT Neuropsychological models of depression highlight temporoparietal hypofunction associated with low emotional arousal in major depressive disorder (MDD). These models were derived from indirect measures such as neuropsychological tests and electroencephalography alpha band power. OBJECTIVE To determine if high-arousing stimuli directly modulated activity in attention and arousal-related sensory brain regions in patients with MDD. DESIGN Between-group comparison (patients with MDD vs healthy control subjects) of neuromagnetic oscillatory activity driven by flickering emotional and neutral pictures (steady-state visual evoked fields [ssVEFs]). SETTING Center of magnetoencephalography at a public university and public ambulatory mental health service. PARTICIPANTS Fifteen female low-anxious patients with MDD and 15 female controls. The groups were matched with respect to age and handedness. INTERVENTION Magnetoencephalographic recordings and self-report ratings. MAIN OUTCOME MEASURES Modulation of current source strengths obtained by frequency domain minimum norm source localization of ssVEFs. RESULTS Controls and patients with MDD showed enhanced current source strengths at ssVEF frequency in occipital and parietal cortex for high-arousing emotional pictures (P < .05 for permutation statistics). While this arousal modulation in controls was pronounced in the right temporoparietal cortex, weak arousal modulation characterized that brain region in patients with MDD (F(1,28) = 7.2, P < .05 for interaction group by quadraticcontrast). CONCLUSIONS Although emotional pictures engaged the dorsal visual stream to a greater extent than neutral pictures in both study groups, only controls showed strong arousal modulation in the right temporoparietal cortex. Because the right temporoparietal cortex is associated with the arousal dimension of emotion, subjects with depression may have difficulties in activating arousal-related brain areas, whereas basic stimulus processing related to activation of the dorsal visual stream is intact.

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

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

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

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

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

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

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.

Association in alcoholic patients between Psychopathic Traits and the additive effect of allelic forms of theCNR1 andFAAH endocannabinoid genes, and the 3′ Region of theDRD2 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 theDRD2 gene, the 10-repeat allele of a variable number tandem repeats (VNTR) of theSLC6A3 gene, the C385AFAAH SNP and the 3′-UTR microsatellite ofCNR1 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 andFAAH 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.

Role of endocannabinoid system in mental diseases

In the last decade, a large number of studies using Δ9-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 on 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 endocannabi-noid system to novel opportunities for therapeutic intervention and its effects on the central nervous system.

Cloninger's typology and treatment outcome in alcohol-dependent subjects during pharmacotherapy with naltrexone

Naltrexone is an opiate receptor antagonist mainly at the µ‐receptor that is thought to reduce the positively reinforcing, pleasurable effects of alcohol and to reduce craving. An increase in time to first relapse to heavy drinking has been the most consistent finding obtained with naltrexone, although not all trials including two of the largest have been positive. Inconsistent outcome data suggest that effectiveness varies among different subgroups of patients. This paper re‐evaluates recent data on the effectiveness of naltrexone in subjects differentiated according to Cloninger Type I and II. Moreover, it combines and cross‐validates results of two recent European studies that found naltrexone treatment more beneficial in alcohol‐dependent patients with early age at onset of drinking problems (Cloninger Type II). It is discussed whether especially these subjects should be targeted for pharmacological relapse prevention treatment with naltrexone.