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ABSTRACT: Inflammatory and immune processes have been implicated in the etiopathology of schizophrenia. We demonstrate the existence of immune function alteration, assessed by serum cytokine's levels, not only in schizophrenia patients but also in their unaffected first-degree relatives. This finding may provide a new data for considering cytokines as schizophrenic disease biomarkers.
Psychiatry Research 07/2012; · 2.52 Impact Factor
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ABSTRACT: 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.
Neurotoxicity Research 04/2012; 11(1):51-59. · 3.51 Impact Factor
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ABSTRACT: Prepulse inhibition (PPI) of startle is an operational measure of the pre-attentive filtering process known as sensorimotor gating. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle inducing stimulus, and reduces the magnitude of the startle response. This experimental paradigm has been studied in laboratory animal as well as in patients with schizophrenia. Recently, PPI deficits have been observed in other psychiatric disorders that shared some deficit in cognitive and sensorimotor gating.
We have reviewed studies examining prepulse inhibition in humans across some neuropsychiatric disorders for asses the clinical and neurobiological implications of this paradigm.
PPI deficits have been observed in multiple psychiatric disorders many of which present a common correlate anatomic-functional and a dysfunction in several neurotransmission systems, mainly dopamine system. These dysfunctions are independent of categorical diagnostic and they have proposed as a biological marker of vulnerability for some psychiatric disorders.
Revista de neurologia 10/2011; 53(7):422-32. · 0.65 Impact Factor
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ABSTRACT: 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.
Biological Psychiatry 02/2011; 128(1-3):15-22. · 8.28 Impact Factor
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ABSTRACT: 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.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2010; 153B(4):948-54. · 3.70 Impact Factor
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ABSTRACT: TaqIA, the most widely analyzed genetic polymorphism in addictions, has traditionally been considered a gene marker for association with D2 dopamine receptor gene (DRD2). TaqIA is located in the coding region of the ANKK1 gene that overlaps DRD2 and encodes a predicted kinase ANKK1. The ANKK1 protein nonetheless had yet to be identified. This study examined the ANKK1 expression pattern as a first step to uncover the biological bases of TaqIA-associated phenotypes.
Northern blot and quantitative reverse-transcriptase polymerase chain reaction analyses were performed to analyze the ANKK1 mRNA. To study ANKK1 protein expression, we developed two polyclonal antibodies to a synthetic peptides contained in the putative Ser/Thr kinase domain.
We demonstrate that ANKK1 mRNA and protein were expressed in the adult central nervous system (CNS) in human and rodents, exclusively in astrocytes. Ankk1 mRNA level in mouse astrocyte cultures was upregulated by apomorphine, suggesting a potential relationship with the dopaminergic system. Developmental studies in mice showed that ANKK1 protein was ubiquitously located in radial glia in the CNS, with an mRNA expression pick around embryonic Day 15. This time expression pattern coincided with that of the Drd2 mRNA. On induction of differentiation by retinoic acid, a sequential expression was found in human neuroblastoma, where ANKK1 was expressed first, followed by that of DRD2. An opposite time expression pattern was found in rat glioma.
Spatial and temporal regulation of the expression of ANKK1 suggest an involvement of astroglial cells in TaqIA-related neuropsychiatric phenotypes both during development and adult life.
Biological psychiatry 10/2009; 67(1):3-11. · 8.93 Impact Factor
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ABSTRACT: 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.
Neurotoxicity Research 08/2009; 16(1):50-9. · 3.51 Impact Factor
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Janet Hoenicka,
Elena Garrido,
Isabel Martínez,
Guillermo Ponce,
María Aragüés, Roberto Rodríguez-Jiménez,
Laura España-Serrano,
Ximena Alvira-Botero,
José Luis Santos,
Gabriel Rubio,
Miguel Angel Jiménez-Arriero,
Tomás Palomo
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ABSTRACT: 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.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2009; 153B(1):79-85. · 3.70 Impact Factor
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ABSTRACT: 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.
To determine the role of 2 laboratory paradigms of impulsivity in the development of alcohol use disorders.
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.
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.
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.
Alcoholism Clinical and Experimental Research 09/2008; 32(9):1681-7. · 3.34 Impact Factor
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ABSTRACT: 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.
Investigación clínica 07/2008; 49(2):195-205.
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ABSTRACT: 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.
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.
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.
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.
The Journal of Clinical Psychiatry 05/2008; 69(4):563-70. · 5.80 Impact Factor
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ABSTRACT: Impulsivity has been associated with alcohol dependence, but impulsivity in alcohol-dependent subjects with a Cluster-B personality disorder (PD) has not been well characterized. Using a variety of laboratory measures of impulsivity, we assessed whether alcohol-dependent patients (ADP) with borderline personality disorder (BPD) exhibited the same pattern of behavioral impulsivity than ADP with antisocial personality disorder (AntPD). Also, differences between ADP without PDs and healthy controls were assessed.
A cross-sectional patient survey with a community comparison group. Diagnoses were made using the Structured Interview for DSM-IV. Sustained attention and rapid-response impulsivity were assessed using the continuous performance test. Inhibitory control was measured by the stop-signal task. Ability to delay reward task was assessed using differential reinforcement for low-rate responding (DRLR). A final sample of 247 males with alcohol-dependence recruited from 2 alcoholism treatment centers was compared with a matched nonsubstance-abusing comparison group (n = 96).
Alcohol-dependent patients with BPD made more omission errors than ADP with AntPD, but individuals with AntPD exhibited the poorest efficiency in DRLR. ADPs with a Cluster-B PD displayed more impairment across all behavioral measures than ADP without PD and than controls. In contrast, with respect to controls ADP without a Cluster-B PD showed more impairment only in DRLR.
Our findings support the suggestion of 2 paradigms in alcohol dependence. The first, based on inability to delay gratification, might be a vulnerability marker for alcohol dependence. The second was related to inhibitory control and might be specific for AntPD and BPDs.
Alcoholism Clinical and Experimental Research 12/2007; 31(11):1826-32. · 3.34 Impact Factor
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ABSTRACT: The relation between alcohol and jealousy is a deeply rooted belief within the general population as well as in the medical, and particularly psychiatric, environment. Furthermore, in recent years there has been a growing interest on the forensic aspects of pathological jealousy, since they are a frequent cause of severe violence, homicide and suicide. Some authors have described a high prevalence of pathological jealousy in alcoholic patients, even awarding it a pathognomonic value in alcoholism. Nevertheless, recent studies do not completely support this relation, and draw attention to other factors. Results from the various studies contain several definitions and classifications of pathological jealousy, and although most of them highlight the prevalence of jealousy in alcoholic patients, they question its pathognomonic quality. Also, the presence of pathological jealousy in subjects with psychiatric disorders other than alcoholism is suggested, indicating the existence of predisposing and triggering factors which could explain the development of pathological jealousy. Yet, the important methodological difficulties in the published articles and the shortage of studies do not allow the confirmation of the alcoholic etiology in pathological jealousy; this is the reason why considering alcoholic jealousy as a separate entity is debatable. In this sense, the best diagnosis in these patients would be paranoid disorder combined with alcoholic dependence, hence, a dual diagnosis.
Adicciones 02/2007; 19(3):267-72. · 0.80 Impact Factor
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ABSTRACT: 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.
Neurotoxicity Research 02/2007; 11(1):61-72. · 3.51 Impact Factor
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ABSTRACT: 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.
Neurotoxicity Research 02/2007; 11(1):51-60. · 3.51 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Medicina Clínica 02/2007; 128(2):41-4. · 1.38 Impact Factor
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ABSTRACT: The cannabinoid receptor 1 gene (CNR1) has been associated with addictive disorders and schizophrenia in different studies. We have compared the frequencies of the alleles for the 3'-UTR CNR1 microsatellite in a sample of 113 Spanish schizophrenic patients, including 68 with comorbid substance abuse, and 111 healthy controls. We report that the frequency of the allele 4 of this microsatellite is significantly lower in schizophrenia patients when compared with controls (chi(2) = 7.858; df 1; P = 0.005). No differences have been found with respect to substance abuse.Thus, the allele 4 represents, in our sample, a protective factor against schizophrenia (odds ratio 0.468, 95% confidence interval (CI) 0.27-0.79). The population attributable genetic risk for the allele 4 absence is 30% (95% CI = 17-41%) and the attributable risk for the allele 4 absence in those with schizophrenia is 53% (95% CI = 20-73%). Our results suggest that, independent of substance abuse, differences in the cannabinoid system function could be involved in the vulnerability to schizophrenia in Spanish population.
European Archives of Psychiatry and Clinical Neuroscience 11/2006; 256(7):437-41. · 3.49 Impact Factor
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Adicciones: Revista de socidrogalcohol, ISSN 0214-4840, Vol. 19, Nº. 3, 2007, pags. 267-272.
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Observatorio de drogodependencias de Castilla-La Mancha, Nº 3, 2007, pags. 95-102.
