Concepción Vaquero-Lorenzo

New perspectives in glutamate and anxiety

Anxiety and stress-related disorders, namely posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (ODC), social and specific phobias, and panic disorder, are a major public health issue. A growing body of evidence suggests that glutamatergic neurotransmission may be involved in the biological mechanisms underlying stress response and anxiety-related disorders. The glutamatergic system mediates the acquisition and extinction of fear-conditioning. Thus, new drugs targeting glutamatergic neurotransmission may be promising candidates for new pharmacological treatments. In particular, N-methyl-d-aspartate receptors (NMDAR) antagonists (AP5, AP7, CGP37849, CGP39551, LY235959, NPC17742, and MK-801), NMDAR partial agonists (DCS, ACPC), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) antagonists (topiramate), and several allosteric modulators targeting metabotropic glutamate receptors (mGluRs) mGluR1, mGluR2/3, and mGluR5, have shown anxiolytic-like effects in several animal and human studies. Several studies have suggested that polyamines (agmatine, putrescine, spermidine, and spermine) may be involved in the neurobiological mechanisms underlying stress-response and anxiety-related disorders. This could mainly be attributed to their ability to modulate ionotropic glutamate receptors, especially NR2B subunits. The aim of this review is to establish that glutamate neurotransmission and polyaminergic system play a fundamental role in the onset of anxiety-related disorders. This may open the way for new drugs that may help to treat these conditions.

Rare Genotype Combination of the Serotonin Transporter Gene Associated With Treatment Response in Severe Personality Disorder

The insertion deletion (ins/del) polymorphism of the serotonin transporter gene (5‐HTTLPR) has been associated with several psychiatric phenotypes and antidepressants response. We investigated, in a large cohort of 5,608 controls and subjects suffering from various psychiatric disorders, the frequency of haplotypes and corresponding genotypes combining the 5‐HTTLPR and the other serotonin transporter promoter functional variant (rs25531). We showed that rs25531 lies 18 bp 5′ to the site where the 43 bp (and not 44 bp as previously described) ins/del defines the 14‐ and 16‐repeat alleles. These polymorphisms should therefore be considered as four alleles instead of a triallelic unique locus. The very rare G‐14/G‐16 genotype was carried on by only three subjects. These are women with a history of suicide attempt with a psychiatric history strongly suggesting a borderline personality disorder. Two of them have shown a non‐response to serotoninergic antidepressant. Interestingly, in one of them was observed a spectacular response after the introduction of bupropion. The genotyping droved our therapeutic approach, by preferring a dopaminergic over a serotoninergic agent. This study highlights the usefulness of studying very rare clinical cases as well as rare variants, in order to deal with the biological heterogeneity of spectral disorders.

Association study of two polymorphisms of the serotonin-2A receptor gene and suicide attempts

Serotonin (5‐HT) receptors may have a role in suicidal behavior. Previous studies have shown an association between the T102C polymorphism of the 5‐HT2a receptor gene and suicidal behavior. However, negative findings have also been reported. We examined the association between the T102C and C1354T (His452Tyr) polymorphisms of the 5‐HT2a receptor gene and suicide attempts. Four hundred forty‐one suicide attempters, 339 psychiatric patients, and 410 healthy controls were compared for genotypes of the T102C and C1354T (His452Tyr) polymorphisms. There were significant differences in the distribution of the three genotypes (TT, TC, and CC) of the T102C polymorphism in the three groups (controls, psychiatric patients, and suicide attempters). There was an excess of C/C genotypes in the suicide attempter group compared with the control group, but there were no significant differences between suicide attempters and psychiatric controls. We found no association between the C1354T polymorphism and suicide attempts. The C allele of the T102C polymorphism of the 5‐HT2A receptor gene may be associated with biological susceptibility for suicidal behavior or psychiatric conditions.

Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population

Risperidone non-compliance is often high due to undesirable side effects, whose development is in part genetically determined. Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results. Thus, the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment: sleepiness, weight gain, extrapyramidal symptoms and sexual adverse events. A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response. Presence of adverse events was the main variable and potential confounding factors were considered. Allele 16Gly of ADRB2 was significantly associated with a higher risk of sexual adverse events. There were other non-significant trends for DRD3 9Gly and SLC6A4 S alleles. Our results, although preliminary, provide new candidate variants of potential use in risperidone safety prediction.

CYP2D6 poor metabolizer status might be associated with better response to risperidone treatment.

The variability in the antipsychotic response is, to some extent, genetically determined. Several studies have attempted to establish a role for genetic variation in genes coding pharmacokinetic and pharmacodynamic targets, but to date, no definite genetic predictive marker has been identified. We aimed to explore the putative role of 19 genetic variants and risperidone clinical improvement in 76 White schizophrenic inpatients, measured as change in Positive and Negative Syndrome Scale (PANSS). CYP2D6 poor metabolism was significantly associated with greater clinical improvement in total PANSS and a trend was also found for MDR1 3435C>T to higher total PANSS scores in 3435T carriers. This study suggests the importance that genetic variability on pharmacokinetic factors may have in risperidone response and gives evidence for the need for further investigation in order to establish the actual predictive value and clinical utility that CYP2D6 genotyping might have in risperidone therapy management.

Positive association between SAT-1 -1415T/C polymorphism and anxiety.

Limbic glutamatergic neurotransmission plays a pivotal role in the pathogenesis of anxiety disorders. Polyamines modulate the activity of several ionotropic glutamate receptors and have been involved in the regulation of fear‐conditioning response. Spermidine/spermine N1‐acetyltransferase (SSAT‐1) is the main enzyme regulating polyamine catabolism. The aim of the present study was to examine the association between anxiety disorders and the −1415T/C (rs1960264) single nucleotide polymorphism (SNP) of the gene (SAT1) coding for SSAT‐1. A case–control design was used in order to compare the genotypes for the −1415T/C (rs1960264) SNP between anxiety patients (n = 218), other non‐anxiety psychiatric patients (n = 362), and healthy controls (n = 251). DSM‐IV diagnoses were provided using MINI 4.4. Genomic DNA was extracted from peripheral blood samples collected from participants. In males, there was a significant difference in the distribution of the two genotypes (T and C) for the SAT‐1 −1415T/C SNP between anxiety patients, non‐anxiety psychiatric controls, and healthy controls. The T genotype was significantly more frequent in males suffering from anxiety disorders than in male psychiatric controls and healthy controls. This is the first study linking polymorphic variants of genes involved in polyamine metabolism with anxiety disorders.

Evaluating a newly developed pharmacogenetic array: screening in a Spanish population

AIMS How genes affect the response in a patient to a given medication is still poorly understood; the validation of biomarkers and technologies need to be performed. This study aims to determine the analytical characteristics of PHARMAChip(®), a newly developed pharmacogenetic array, and the Spanish population allelic and genotypic frequencies of the genetic variants included in this chip. MATERIALS & METHODS The analytical characteristics of PHARMAChip assessed were sensitivity and specificity (for CYP2D6 and SLC6A4), accuracy (for SLC6A4) and genotyping rate: frequencies of the 90 pharmacogenetic variants of 36 genes were included in PHARMAChip. These were compared in 449 Spanish subjects with data reported in Caucasians. RESULTS & CONCLUSION Sensitivity and specificity ranged from 96-100%, accuracy was 94.8% and genotyping success rate was 99.6%. PHARMAChip is an accurate, rapid and updatable tool, which may be especially useful for cytochrome P450 testing. The allelic and genotypic frequencies found in the Spanish subjects reinforce the need for establishing possible intraethnic differences among populations prior to performing this kind of study.

Nucleotide variation in central nervous system genes among male suicide attempters

Despite marked morbidity and mortality associated with suicidal behavior, accurate identification of individuals at risk remains elusive. The goal of this study is to identify a model based on single nucleotide polymorphisms (SNPs) that discriminates between suicide attempters and non‐attempters using data mining strategies. We examined functional SNPs (n = 840) of 312 brain function and development genes using data mining techniques. Two hundred seventy‐seven male psychiatric patients aged 18 years or older were recruited at a University hospital psychiatric emergency room or psychiatric short stay unit. The main outcome measure was history of suicide attempts. Three SNPs of three genes (rs10944288, HTR1E; hCV8953491, GABRP; and rs707216, ACTN2) correctly classified 67% of male suicide attempters and non‐attempters (0.50 sensitivity, 0.82 specificity, positive likelihood ratio = 2.80, negative likelihood ratio = 1.64). The OR for the combined three SNPs was 4.60 (95% CI: 1.31–16.10). The models accuracy suggests that in the future similar methodologies may generate simple genetic tests with diagnostic utility in identification of suicide attempters. This strategy may uncover new pathophysiological pathways regarding the neurobiology of suicidal acts.

Genetic epistasis in female suicide attempters

BACKGROUND Complex behaviors such as suicidal behavior likely exhibit gene-gene interactions. The main aim of this study is to explore potential single nucleotide polymorphisms combinations with epistatic effect in suicidal behavior using a data mining tool (Multifactor Dimensionality Reduction). METHODS Genomic DNA from peripheral blood samples was analyzed using SNPlex Technology. Multifactor Dimensionality Reduction was used to detect epistatic interactions between single nucleotide polymorphisms from the main central nervous system (CNS) neurotransmitters (dopamine: 9; noradrenaline: 19; serotonin: 23; inhibitory neurotransmitters: 60) in 889 individuals (417 men and 472 women) aged 18 years or older (585 psychiatric controls without a history of suicide attempts, and 304 patients with a history of suicide attempts). Individual analysis of association between single nucleotide polymorphisms and suicide attempts was estimated using logistic regression models. RESULTS Multifactor Dimensionality Reduction showed significant epistatic interactions involving four single nucleotide polymorphisms in female suicide attempters with a classification test accuracy of 60.7% (59.1%-62.4%, 95% CI): rs1522296, phenylalanine hydroxylase gene (PAH); rs7655090, dopamine receptor D5 gene (DRD5); rs11888528, chromosome 2 open reading frame 76, close to diazepam binding inhibitor gene (DBI); and rs2376481, GABA-A receptor subunit γ3 gene (GABRG3). The multivariate logistic regression model confirmed the relevance of the epistatic interaction [OR(95% CI)=7.74(4.60-13.37)] in females. CONCLUSIONS Our results suggest an epistatic interaction between genes of all monoamines and GABA in female suicide attempters.

CYP2D6 POLYMORPHISM AND MENTAL AND PERSONALITY DISORDERS IN SUICIDE ATTEMPTERS

Prior studies on the association between the CYP2D6 polymorphism and suicide did not explore whether mental and personality disorders mediate this association. The main objective of the present study was to test an association between CYP2D6 polymorphism and mental and personality disorders among suicide attempters. The MINI and the DSM-IV version of the International Personality Disorder Examination Screening Questionnaire were used to diagnose mental and personality disorders, respectively, in 342 suicide attempters. Suicide attempters were divided into four groups according to their number of CYP2D6 active genes (zero, one, and two or more). Differences in mental and personality disorders across the four groups were measured using linear-by-linear association, chi square-test, and 95% confidence intervals. Suicide attempters carrying two or more active CYP2D6 genes were more likely to be diagnosed with at least one personality disorder than those with one or zero CYP2D6 active genes.