[Analysis of polymorphism rs1051730 of CHRNA3 in patients with dual pathology in a Mexican population]. / Analisis del polimorfismo rs1051730 de CHRNA3 en pacientes con patologia dual en poblacion mexicana.

INTRODUCTION: Epidemiological studies have described a high comorbidity of substance use disorders with another psychiatric disorder, which has been called dual pathology. However, the aetiological mechanisms underlying this association are still not fully understood. AIM: To carry out a preliminary study of the effect of polymorphism rs1051730 of the gene group CHRNA5-CHRNA3-CHRNB4 through a case-control study. SUBJECTS AND METHODS: A total of 225 subjects were selected and divided into three groups: those diagnosed with bipolar disorder, those with nicotine dependence, and subjects without nicotine dependence or any other psychiatric disorder. Genotyping was performed by real-time polymerase chain reaction. Genetic association analysis was performed using chi-square tests and multivariate logistic regressions. RESULTS: On comparing allelic frequencies with the control group, we found that polymorphism rs1051730 was associated with nicotine dependence (p = 0.03), but not with bipolar disorder (p = 0.94). CONCLUSION: Variant rs1051730 was associated with nicotine dependence in the Mexican population and showed the same effect in dual pathology. However, further studies are recommended to obtain conclusive results.

TITLE: Analisis del polimorfismo rs1051730 de CHRNA3 en pacientes con patologia dual en poblacion mexicana.Introduccion. Estudios epidemiologicos han descrito una alta comorbilidad de los trastornos de uso de sustancias con otro trastorno psiquiatrico, al cual se le ha llamado patologia dual. Sin embargo, los mecanismos etiologicos de esta asociacion continuan siendo dificiles de entender. Objetivo. Realizar un estudio preliminar del efecto del polimorfismo rs1051730 del grupo de genes CHRNA5-CHRNA3-CHRNB4 a traves de un estudio de casos y controles. Sujetos y metodos. Se selecciono a un total de 225 sujetos, divididos en tres grupos: con diagnostico de trastorno bipolar, con dependencia a la nicotina y sujetos sin dependencia a la nicotina o cualquier otro trastorno psiquiatrico. La genotipificacion se realizo mediante reaccion en cadena de la polimerasa en tiempo real. El analisis de asociacion genetica se realizo mediante pruebas de chi cuadrado y regresiones logisticas multivariables. Resultados. Al comparar las frecuencias alelicas con el grupo control, encontramos que el polimorfismo rs1051730 se asocio con el grupo de dependencia a la nicotina (p = 0,03), pero no con el de trastorno bipolar (p = 0,94). Conclusion. La variante rs1051730 se asocio con dependencia a la nicotina en la poblacion mexicana y mostro el mismo efecto en la patologia dual. Sin embargo, se recomiendan estudios adicionales para tener resultados concluyentes.

Improvement of psychic and somatic symptoms in adult patients with generalized anxiety disorder: examination from a duloxetine, venlafaxine extended-release and placebo-controlled trial.

BACKGROUND: This study examined the efficacy and tolerability of duloxetine and venlafaxine extended-release (XR) treatment for generalized anxiety disorder (GAD), with a secondary focus on psychic and somatic symptoms within GAD. METHOD: The design was a 10-week, multi-center, double-blind placebo-controlled study of duloxetine (20 mg or 60-120 mg once daily) and venlafaxine XR (75-225 mg once daily) treatment. Efficacy was measured using the Hamilton Anxiety Rating Scale (HAMA), which includes psychic and somatic factor scores. Tolerability was measured by occurrence of treatment-emergent adverse events (TEAEs) and discontinuation rates. RESULTS: Adult out-patients (mean age 42.8 years; 57.1% women) with DSM-IV-defined GAD were randomly assigned to placebo (n=170), duloxetine 20 mg (n=84), duloxetine 60-120 mg (n=158) or venlafaxine XR 75-225 mg (n=169) treatment. Each of the three active treatment groups had significantly greater improvements on HAMA total score from baseline to endpoint compared with placebo (p=0.01-0.001). For the HAMA psychic factor score, both duloxetine treatment arms and venlafaxine XR demonstrated significantly greater improvement compared with placebo (p=0.01-0.001). For the HAMA somatic factor score, the mean improvement in the duloxetine 60-120 mg and venlafaxine XR groups was significantly greater than placebo (p0.05 and p0.01 respectively), whose mean improvement did not differ from the duloxetine 20 mg group (p=0.07). Groups did not differ in study discontinuation rate due to adverse events. CONCLUSIONS: Duloxetine and venlafaxine treatment were each efficacious for improvement of core psychic anxiety symptoms and associated somatic symptoms for adults with GAD.

The serotonin transporter 5-HTTPR polymorphism is associated with current and lifetime depression in persons with chronic psychotic disorders.

OBJECTIVE: Variation in the serotonin transporter gene (SLC6A4) promoter region has been shown to influence depression in persons who have been exposed to a number of stressful life events. METHOD: We evaluated whether genetic variation in 5-HTTLPR, influences current depression, lifetime history of depression and quantitative measures of depression in persons with chronic psychotic disorders. This is an association study of a genetic variant with quantitative and categorical definitions of depression conducted in the southwest US, Mexico and Costa Rica. We analyzed 260 subjects with a history of psychosis, from a sample of 129 families. RESULTS: We found that persons carrying at least one short allele had a statistically significant increased lifetime risk for depressive syndromes (P < 0.02, odds ratio 2.18, 95% CI 1.10-4.20). CONCLUSION: The 'ss' or 'sl' genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of psychotic individuals to develop major depression during the course of their illness.

Neuromodulation of the inferior thalamic peduncle for major depression and obsessive compulsive disorder.

Neuromodulation of the inferior thalamic peduncle is a new surgical treatment for major depression and obsessive-compulsive disorder. The inferior thalamic peduncle is a bundle of fibers connecting the orbito-frontal cortex with the non-specific thalamic system in a small area behind the fornix and anterior to the polar reticular thalamic nucleus. Electrical stimulation elicits characteristic frontal cortical responses (recruiting responses and direct current (DC)-shift) that confirm correct localization of this anatomical structure. A female with depression for 23 years and a male with obsessive-compulsive disorder for 9 years had stereotactic implantation of electrodes in the inferior thalamic peduncle and were evaluated over a long-term period. Initial OFF stimulation period (1 month) showed no consistent changes in the Hamilton Depression Scale (HAM-D), Yale Brown Obsessive Compulsive Scale (YBOCS), or Global Assessment of Functioning scale (GAF). The ON stimulation period (3-5 V, 130-Hz frequency, 450-msec pulse width in a continuous program) showed significant decrease in depression, obsession, and compulsion symptoms. GAF improved significantly in both cases. The neuropsychological tests battery showed no significant changes except from a reduction in the perseverative response of the obsessive-compulsive patient and better performance in manual praxias of the female depressive patient. Moderate increase in weight (5 kg on average) was observed in both cases.

A genome-wide scan for schizophrenia and psychosis susceptibility loci in families of Mexican and Central American ancestry.

Schizophrenia is a complex psychiatric disorder, likely to be caused in part by multiple genes. In this study, linkage analyses were performed to identify chromosomal regions most likely to be associated with schizophrenia and psychosis in multiplex families of Mexican and Central American origin. Four hundred and fifty-nine individuals from 99 families, containing at least two siblings with hospital diagnoses of schizophrenia or schizoaffective disorder, were genotyped. Four hundred and four microsatellite markers were genotyped for all individuals and multipoint non-parametric linkage analyses were performed using broad (any psychosis) and narrow (schizophrenia and schizoaffective disorder) models. Under the broad model, three chromosomal regions (1pter-p36, 5q35, and 18p11) exhibited evidence of linkage with non-parametric lod (NPL) scores greater than 2.7 (equivalent to empirical P values of less than 0.001) with the peak multipoint NPL = 3.42 (empirical P value = 0.00003), meeting genomewide evidence for significant linkage in the 1pter-p36 region. Under the narrow model, the same three loci showed (non-significant) evidence of linkage. These linkage findings (1pter-p36, 18p11, and 5q35) highlight where genes for psychosis and schizophrenia are most likely to be found in persons of Mexican and Central American ancestry, and correspond to recent linkages of schizophrenia or psychosis in other populations which were formed in part from emigrants from the Spanish empire of the 15th and 16th centuries.

Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism.

Allelic variants in the promoter region of the serotonin transporter (5-HTT) gene have been implicated in several psychiatric disorders and personality traits. In particular, two common alleles in a variable repeat sequence of the promoter region (SLC6A4) have been differentially associated with a display of abnormal levels of anxiety and affective illness in individuals carrying the "s" allele. The aim of this study was to compare the basal cerebral metabolic activity of non-psychiatric subjects in fronto-limbic structures to determine whether differences exist in basal metabolic activity within this functional polymorphism. PET scans with fluorine-18 fluorodeoxyglucose as radiotracer were performed in 71 non-psychiatric subjects previously screened for psychopathology and subsequently genotyped for SLC6A4; PET images were compared with SPM2 according to s/s (n = 27), s/l (n = 25), and l/l (n = 19) groups considering a significance threshold in a priori selected areas of P < 0.001 and an extent threshold > or =5 voxels. The analysis showed an effect of interest among the three genotype groups in right anterior cingulate gyrus (ACC), left middle frontal gyrus, and left posterior cingulate gyrus (PCC). Comparison between l/l vs. s/s showed increased metabolism for l/l in left middle frontal gyrus and an increase for s/s in right ACC and left PCC. Comparison between s/s vs. s/l showed an increase for s/s in left PCC and right ACC. Increased basal metabolism in fronto-limbic structures for the s/s group may be conceived as an "overactive metabolic state" of these structures, possibly related to an increased susceptibility for developing an anxiety-depression spectrum disorder.

[Sensitivity and specificity of a neuropsychological instrument in the evaluation of schizophrenia subtypes: a study with a Spanish speaking population]. / Sensibilidad y especificidad de un instrumento neuropsicológico en la evaluación de subtipos de esquizofrenia: un estudio con población hispanohablante.

INTRODUCTION: Cognitive impairment is a prominent feature of schizophrenia that correlates with functional outcome. In the clinical practice and research, there is a need to count on brief, reliable and standardized instruments to evaluate the cognitive profile in psychiatric, geriatric and neurological patients. There are only a few standardized and validated instruments with the Hispanic population, so the adaptation and validation of instruments become a high relevance issue. The Brief Neuropsychological Test in Spanish (NEUROPSI) is a brief neuropsychological battery evaluating a wide spectrum of cognitive functions and standardized with Spanish speaking population according to age and educational level. The purpose of the present study was to determine the sensitivity and specificity of this instrument for its clinical use in patients with schizophrenia, as well as in distinct subtypes of schizophrenic patients: positive, negative and mixed. METHODS: We studied a total sample of 60 subjects (30 patients with schizophrenia and 30 matched controls). Using the total score we found 87.5 % sensitivity and 92.8% specificity. A discriminant analysis using the 25 subtest scores of the NEUROPSI accurately classified 83.3 % of the sample. None of the control subjects was classified as patient. RESULTS: Classification by subtype showed 80 % of patients with negative symptoms, 90 % of patients with positive symptoms and 70 % of patients with mixed symptoms. CONCLUSIONS: The accurate diagnosis of cognitive dysfunction in schizophrenic patients could help in management as well as development of more specific pharmacological treatment for each schizophrenic subtype.

A forced five-dimensional factor analysis and concurrent validity of the Positive and Negative Syndrome Scale in Mexican schizophrenic patients.

UNLABELLED: The heterogeneity of schizophrenic symptomatology is well documented. The positive-negative distinction is limited to cover the entire spectrum of schizophrenic psychopathology in order to describe the various clinical aspects of the disorder. METHOD: We recruited 150 schizophrenic patients between May 2002 and September 2003. Diagnoses were based on a structured clinical interview. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate general psychopathology and symptom severity. For the concurrent validity of the pentagonal model of the PANSS, the BPRS, the CDSS, the OAS and the MMSE were used. RESULTS: The forced five-factor principal-component analysis explained 53.4% of the total variance. There were significant correlations between the clinical rating scales and the five components of the PANSS. DISCUSSION: Our data support a pentagonal model underlying the multidimensional schizophrenic symptomatology as assessed by the PANSS. The five-factor structure of the PANSS in Mexican schizophrenic patients enables further elucidation of the various clinical aspects of schizophrenia.

Premorbid adjustment and violent behavior in schizophrenic patients.

UNLABELLED: We examined the influence of premorbid adjustment on violent behavior in schizophrenic patients. There is some evidence that poor premorbid adjustment predicts violent behavior, then we decided to examine this hypothesis further. METHOD: We recruited 72 schizophrenic patients without concomitant substance abuse 6 months prior to the assessment. Diagnoses were based on the SCID-I. Premorbid adjustment was evaluated with the Premorbid Adjustment Scale and violent behaviors with the Overt Aggression Scale. RESULTS: Violent schizophrenic patients showed an overall worse premorbid adjustment during childhood. In addition, the area of "peer relationships" was significantly diminished in several life period sections such as childhood, early and late adolescence in violent patients. DISCUSSION: Our data indicate that difficulties in social relationships during early stages of life may increase the risk of future violent behavior among schizophrenic patients.

[Validity and reliability of the Spanish version of Yale-Brown obsessive-compulsive rating scale for children and adolescents]. / Estudio de validez y confiabilidad de la versión en español de la escala Yale-Brown del trastorno obsesivo-compulsivo para niños y adolescentes.

INTRODUCTION: The Children Yale-Brown Obsessive- Compulsive Scale (CY-BOCS) constitutes a very good instrument for the evaluation of obsessive-compulsive disorder (OCD) symptoms, by a clinical interview administered to the patient and parent, that includes summary score of the clinician. OBJECTIVE: We are proposing a Spanish version of instrument, which is rated during a brief clinical interview to the parents and the patients. We are presenting data reliability and validity using two out-patient samples. METHODS: After the translation to Spanish, a back translation and adaptation to Spanish of the CY-BOCS, twenty eight out-patients (75 % male) with a mean age 12.1 (+/- 2.7) from two clinical settings on Mexico City evaluated. Reliability was evaluated by computing the internal consistency (Cronbach's alpha) on all interviews. assess interrater agreement, the interviews were videotaped and scored by three independent raters and all of them included both the child and the parent interview. The CY-BOCS total scored was correlated with the K-SADS-PL diagnosis. RESULTS: The CY-BOCS total score for all subjects was 16.5 +/- 9.8. Cronbach's alpha coefficient was 0.87; Pearson correlation of total CY-BOCS score with the K-SADS-PL diagnosis was 0.60 (p < or = 0.05). The intraclass correlations coefficients for the parents, youngsters and clinician 0.96, 0.94 and 0.92, respectively. CONCLUSIONS: The Spanish version of the CY-BOCS reliable and valid instrument, useful for both clinicians and researchers in child and adolescent OCD assessment.

Mu opioid receptor gene as a candidate for the study of obsessive compulsive disorder with and without tics.

Obsessive compulsive disorder (OCD) is a complex psychiatric disease characterized by recurring obsessions or compulsions that cause significant distress to the patient. The etiology of this disorder remains largely unknown, although a genetic component has been suggested. Many candidates genes have been evaluated based on a possible serotoninergic and dopaminergic brain dysfunction. We postulate the micro opioid receptor (MOR) gene as a candidate because some observations support a role of the opioid system in OCD. The opioid antagonist, naloxone, rapidly exacerbates OCD symptoms and the opioid agonist, tramadol, was reported to be effective in the treatment of some patients. We studied two single nucleotide polymorphisms (C17T and A118G) in 51 trios with OCD. Genotyping was analyzed with transmission desequilibrium test (TDT). The allelic variant +17T of the C17T polymorphism had a low frequency (1%) in our population that did not allow for statistic analysis. However, for the allelic variant +G of the A118G polymorphism we were able to performed statistical comparisons. Our results showed a trend toward significance (chi(2) McNemar = 3.6, P = 0.065) for TDT in patients with comorbid tics. It is an interesting finding that should be tested in a larger sample of OCD patients with tics.

[Sensitivity and specificity of the Overt Aggression Scale in schizophrenic patients]. / Sensibilidad y especificidad de la Escala de Agresión Explícita en pacientes con esquizofrenia.

INTRODUCTION: Research focused on the assessment of violent behavior in schizophrenic patients has been hindered by the lack of clinical instruments adapted to the Mexican psychiatric population. This study aimed to obtain sensitivity and specificity data as well as the most adequate cutoff point of the Overt Aggression Scale (OAS). METHOD: 137 schizophrenic patients were included. A clinical evaluation was performed with the PANSS subscale of excitability and the OAS. Diagnosis of violent behavior was obtained with the PANSS and clinical consensus of two psychiatrists. RESULTS: 66.4% of the sample was considered as nonviolent patients. A cutoff point of 7 points in the OAS showed sensitivity of 0.80 and specificity of 0.97, with adequate positive and negative predictive power. DISCUSSION: The objective assessment of violent behavior in schizophrenic patients can contribute to the development of new lines of research. Adaptation of the OAS for the assessment of violent behavior will encourage the development of better strategies for the detection and intervention of violent behavior in schizophrenia.

Association study of the serotonin transporter gene polymorphism in obsessive-compulsive disorder.

The hypothesis implicating the serotonergic system in the pathophysiology of obsessive-compulsive disorder (OCD) is supported by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). Since SSRIs act on the serotonin transporter (5-HTT), it has been suggested that the 5-HTT gene (SCL6A4) could be a good candidate for OCD. The SCL6A4 gene has a 44-bp insertion/deletion polymorphism in its promoter region (5-HTTLPR). Previous studies have revealed an association between OCD and the l allele. We analysed the 5-HTTLPR polymorphic system in 115 Mexican OCD patients and 136 controls. No significant association was found between l allele and OCD (chi2 = 1.54, d.f. = 1, p = 0.21). Furthermore, we assessed alternative methods that employ family-based designs in a sample of 43 trios. Haplotype-based haplotype relative risk and transmission disequilibrium analysis did not show a preferential transmission of l allele to OCD probands. Our results indicate the need to analyse larger samples using family-based methods.

Dopamine D4 receptor (DRD4) gene polymorphism in the first psychotic episode.

BACKGROUND: Dopamine D4 receptor (DRD4) has shown some interesting properties at genetic and possibly functional levels. It has been suggested that some molecular variants of the DRD4 gene (e.g., four and seven alleles) could be implicated in the pathogenesis of psychotic disorders. Additionally, the VNTR polymorphism could be implicated in part of the response to treatment with neuroleptics. This study tested the possible association between the 48-bp tandem repeats in exon 3 of the DRD4 gene and patients experiencing their first psychotic episode. METHODS: Patients with a first psychotic episode (FPE, n = 37) were diagnosed and compared with a matched control group (n = 37). The FPE group was subdivided into two categories: those with nonaffective and those with affective psychoses. The variable number of tandem repeats (VNTR) region of the DRD4 gene was amplified by PCR procedures. Chi-square statistics and appropriate corrections and adjustments were used for data analysis. CONCLUSIONS: A significantly lower frequency of the four repeat (4-R) carriers in the FPE group was observed. This association was sustained mainly by the affective psychotic group (chi2 = 9.99 df = 2, p = 0.0073). Although these results require testing with stringent methods, it is suggested that the DRD4-4R allele may confer some protection against psychosis, mainly of the affective subtype.

Lack of association of apolipoprotein E polymorphism in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) could be considered a neurodevelopmental disorder, from several lines of evidence. One of the most widely studied genes in these disorders is the apolipoprotein E gene, particularly allele 4. We analyzed for association among patients with OCD versus normal controls and cognitively impaired patients. There were no significant differences between OCD probands compared with population controls. However, the cognitively impaired group showed a higher frequency of allele apolipoprotein E gene compared with normal controls and patients with OCD.

[Dopamine D2 and D4 receptor genes distinguish the clinical presence of tics in obsessive-compulsive disorder]. / Los genes de los receptores a dopamina D2 y D4 distinguen la presencia clínica de tics en el trastorno obsesivo-compulsivo.

An allelic association study between dopamine receptor gene polymorphisms D2 (DRD2) and D4 (DRD4), in obsessive-compulsive patients (OCD) with or without chronic motor or vocal tics (OCD+ or OCD-) was performed. Molecular genotypes were obtained using the polymerase chain reaction method (PCR) in 66 patients diagnosed according DSMIV criteria, 12/66 OCD patients presented tics, 54 Control subjects were also typed. OCD patients with tics compared to control had a higher frequency of TaqI A2 allele (p = 0.014); and an excess of homozygous individuals A2A2 (p = 0.001). In DRD4 genes polymorphisms, allele 7 showed a higher prevalence and frequency in those OCD+ tics compared to OCD- tics (91% vs. 48%). Most of the OCD patients with tics compared to those without tics showed an increased frequency of the DRD2-A2 (58% vs 27% respectively, p = 0.048) as well as an increased frequency of the DRD4-7-fold variant (48% in OCD with tics vs 9% in OCD without tics, p = 0.018). Similarly, when both alleles were combined (at least one copy of DRD2-A2 and DRD4-R7), patients with tics showed a higher frequency of this haplotype (83.3% vs. 40%, p = 0.016). OCD patients with tics may represent a different clinical and genetic subtype of the disorder.

The dopamine D2 receptor gene TaqI A1 polymorphism and alcoholism in a Mexican population.

The suggested association between the TaqI A1 allele of the dopamine D2 receptor (DRD2) gene with alcoholism was studied comparing the genotypes of 38 controls and 38 ethnic matched alcoholics, drawn from the Mexican population. The alcoholics in our sample suffered from one of the following conditions: delirium tremens, alcohol hallucinosis or uncomplicated alcohol withdrawal. Eighty-eight percent of the controls carried the A1 allele. The frequency of the DRD2 A1 allele in the Mexican sample was higher than reported in Caucasians, but similar to those described in Amerindian groups. There was not any difference in the prevalence or allele frequency between alcoholics and controls. Also, there was no significant differences when alcoholics were subtyped according to severity, age of onset, or positive family history. Alcoholics showed higher scores than controls in the neuroticism and psychoticism subscales on the Eysenck Personality Inventory. However, no relationship between personality traits and genotypes was found. Our results do not support a consistent association between the D2 receptor gene and alcoholism.

Molecular analysis of the phenylalanine hydroxylase gene in Mexican phenylketonuric patients.

The molecular analysis of the human phenylalanine hydroxylase (PAH) gene in Mexican phenylketonuric (PKU) patients is described. We analyzed the restriction fragment length polymorphism (RFLP) haplotypes of five probands and ten non-affected relatives, belonging to four unrelated PKU families. Twenty-nine alleles were typified, corresponding to 12 different haplotypes. Eight RFLP haplotypes corresponded to those described in other populations, while the remaining were unreported haplotypes, appearing both on normal and PKU chromosomes. Using the polymerase chain reaction (PCR) and the allele-specific oligonucleotide assay (ASO), we also screened for the IVS10 mutation, one of the most common PAH gene mutations in Mediterranean countries. Forty-two percent of the PKU chromosomes analyzed bore the IVS10 mutation, although it was present in the heterozygous state in all cases. Our data show an important genetic heterogeneity at the PAH locus in the Mexican population, and report the genetic influence of the Spanish immigration to the American continent.