Jose Carlos González

Left orbitofrontal and superior temporal gyrus structural changes associated to suicidal behavior in patients with schizophrenia

Suicidal attempts are relatively frequent and clinically relevant in patients with schizophrenia. Recent studies have found gray matter differences in suicidal and non-suicidal depressive patients. However, no previous neuroimaging study has investigated possible structural abnormalities associated to suicidal behaviors in patients with schizophrenia. A whole-brain magnetic resonance voxel-based morphometric examination was performed on 37 male patients meeting the DSM-IV criteria for schizophrenia. Thirteen (35.14%) patients had attempted suicide. A non-parametric permutation test was computed to perform the comparability between groups. An analysis of covariance (AnCova) model was constructed with a statistical threshold of p<0.05 corrected for multiple comparisons. After controlling for age and severity of illness, results showed significant gray matter density reduction in left superior temporal lobe (p=0.03) and left orbitofrontal cortex (p=0.04) in patients who had attempted suicide when comparing with non-suicidal patients. Although sample size limitations and potential clinical heterogeneity preclude definitive conclusions, these data point to structural differences in key cerebral areas. Neuroimaging studies are necessary to expand our knowledge of biological mechanisms underlying suicide in schizophrenia.

Emotional words induce enhanced brain activity in schizophrenic patients with auditory hallucinations

Neuroimaging studies of emotional response in schizophrenia have mainly used visual (faces) paradigms and shown globally reduced brain activity. None of these studies have used an auditory paradigm. Our principal aim is to evaluate the emotional response of patients with schizophrenia to neutral and emotional words. An auditory emotional paradigm based on the most frequent words heard by psychotic patients with auditory hallucinations was designed. This paradigm was applied to evaluate cerebral activation with functional magnetic resonance imaging (fMRI) in 11 patients with schizophrenia with persistent hallucinations and 10 healthy subjects. We found a clear enhanced activity of the frontal lobe, temporal cortex, insula, cingulate, and amygdala (mainly right side) in patients when hearing emotional words in comparison with controls. Our findings are consistent with other studies suggesting a relevant role for emotional response in the pathogenesis and treatment of auditory hallucinations.

Association Study of Nonsynonymous Single Nucleotide Polymorphisms in Schizophrenia

BACKGROUND Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs). METHODS We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures. RESULTS The 5 independent nsSNPs with false discovery rate q ≤ .25, as well as 13 additional nsSNPs at p < .01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10(-6), allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility. CONCLUSIONS Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.

Enantioselective synthesis of (S)-α-methylphenylalanine using (S)-BINOLAMs as new phase-transfer catalysts

Abstract A series of (S)-bis(aminomethyl)binaphthols [(S)-BINOLAMs] 4 have been prepared and used as catalysts in the enantioselective C-alkylation reaction of the aldimine Schiff bases of alanine esters 5 under solid–liquid phase-transfer catalysis (PTC) conditions employing NaOH as base in toluene at room temperature. (S)-3,3′-Bis[(diethylamino)methyl]-2,2′-dihydroxy-1,1′-binaphthalene 4a gave the best e.e.s. (S)-α-Methylphenylalanine 7 was isolated, after hydrolysis of the iminoester, in 85% yield with an e.e. of 68%.

FOXP2 polymorphisms in patients with schizophrenia

BACKGROUND FOXP2 was described as the first gene involved in our ability to acquire spoken language. The main objective of this study was to compare the distribution of FOXP2 gene polymorphisms between patients with schizophrenia and healthy controls. METHODS Two FOXP2 polymorphisms, Intron3a and SNP 923875, and the G-->A transition in exon 14 were analysed in 149 patients with schizophrenia and schizoaffective disorders according to DSM-IV, as well as in 137 controls. All the patients showed a history of auditory hallucinations. RESULTS The transition G-->A at exon 14, detected in all the affected members in KE family, was not found in any of the analyzed samples from patients or controls. No significant differences were found between individual controls and patients for the two analysed polymorphisms. CONCLUSIONS This study would not support a possible role of the two FOXP2 analyzed polymorphisms in the vulnerability to schizophrenia.

Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain

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=1.7×10(-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.

Serotonin transporter gene polymorphism (5-HTTLPR) and emotional response to auditory hallucinations in schizophrenia

The serotonin transporter (5-HTT) has a crucial function in the regulation of serotonin (5-HT) reuptake in presynaptic neurons. 5-HT is a major modulator of emotional behaviour and circadian rhythms. In addition to its neurotransmitter role, it is also an important regulator of morphogenetic activities during early brain development as well as during adult neurogenesis and plasticity (Murphy et al., 2001).

Insight among psychotic patients with auditory hallucinations

Poor insight in psychosis has been described as a seeming lack of awareness of the deficits, consequences of the disorder, and of the need for treatment. The aim of this study is to investigate whether patients with auditory hallucinations have less insight than those without hallucinations, and to determine which hallucination characteristics are related to patient insight. Using the PANSS and PSYRATS, the authors have evaluated the lack of insight data corresponding to 168 psychotic patients divided into three groups: patients with a history of nonpersistent hallucinations, patients with persistent hallucinations, and patients without hallucinations. Patients with persistent hallucinations showed significantly less insight than patients without persistent hallucinations and patients without hallucinations, the farther away the hallucination is located, the greater the lack of patient insight. Patients who hear the hallucination inside their head rather than outside show better insight, possibly because such patients can understand the voice as being created by their own mind.

GENDER DIFFERENCES IN AUDITORY HALLUCINATIONS IN SCHIZOPHRENIA

Introduction: Gender differences in the clinical presentation of patients with schizophrenia have been well documented, yet few studies have investigated gender-related clinical differences of auditory hallucinations in schizophrenia. We compared a group of men and women schizophrenics with auditory hallucinations (AH) in order to evaluate the possibility of characterizing relevant dimensions in this symptom between genders. Methods: The Psychotic symptom rating scale (PSYRATS) for auditory hallucinations was administered to 123 patients (86 men, 37 women) who met DSM-IV criteria for schizophrenia with AH. Patients were also assessed about demographic variables, including age of onset and whether AH were persistent. Results: The results showed that women had greater scores in the dimension “beliefs re-origin” (p<0.034) of the PSYRATS, having a more delusional interpretation about the origin of voices, while men had more persistent AH (p<0.026) and an earlier age of onset (p<029). Conclusions: The findings of our study suggest that gender differences contribute to some dimensions of auditory verbal hallucinations despite the lack of more expected remarkable differences between men and women patients with schizophrenia. References [1] Rector NA, Seeman MV. Auditory hallucinations in women and men.