RÉSUMÉ
BACKGROUND: Women with Premenstrual Dysphoric Disorder (PMDD) are more likely to have a history of childhood trauma, and may experience more severe premenstrual symptomatology. However, the pathway in which childhood trauma affects the prevalence and severity of premenstrual symptoms remains largely unclear. OBJECTIVE: To determine whether childhood trauma is associated with increased premenstrual symptoms, and if so, whether emotional dysregulation mediates or moderates this relationship. PARTICIPANTS AND SETTINGS: A total of 112 women were recruited for the study among students at the Hebrew University of Jerusalem. METHODS: Participants completed the Premenstrual Symptoms Screening Tool (PSST), the Childhood Trauma Questionnaire (CTQ) and the Difficulties in Emotion Regulation Scale (DERS). To test the mediation hypothesis, direct and indirect effects of childhood trauma on premenstrual symptoms were calculated. To test moderation, we performed multiple regression, including the interaction term between childhood trauma and emotion dysregulation RESULTS: Twenty-two women (18.6%) met criteria for premenstrual syndrome (PMS) and sixteen (13.6 %) for PMDD. The number and severity of premenstrual symptoms increased with more childhood trauma (r = .282), and this relationship was completely mediated by emotion regulation difficulties. Specifically, exposure to Sexual abuse (r = .243) and Emotional neglect (r = .198) were significantly associated with premenstrual symptoms. Abuse predicted greater emotion dysregulation (r = .33), whereas, neglect did not. CONCLUSIONS: This study contributes to the current knowledge on the long-term effects of childhood trauma. Promoting use of adaptive emotion regulation strategies for women with a history of childhood trauma, could improve their capability to confront and adapt to premenstrual changes.
Sujet(s)
Maltraitance des enfants/psychologie , Régulation émotionnelle , Trouble dysphorique prémenstruel/psychologie , Plaies et blessures/complications , Adulte , Enfant , Femelle , Humains , Trouble dysphorique prémenstruel/épidémiologie , Syndrome prémenstruel/épidémiologie , Syndrome prémenstruel/psychologie , Prévalence , Autorapport , Enquêtes et questionnaires , Plaies et blessures/psychologie , Jeune adulteRÉSUMÉ
In sorrow thou shalt bring forth children (Genesis 3:16) seems as relevant today, with one of seven mothers afflicted by a depressive episode, constituting the most common medical complication after delivery. Why mothers are variably affected by mood symptoms postpartum remains unclear, and the pathogenesis and early molecular indicators of this divergent outcome have not been described. We applied a case-control design comparing differential global gene expression profiles in blood mononuclear cells sampled shortly after delivery at the time of inception of postpartum depression (PD). Nine antidepressant naive mothers showing high depressive scores and developing a persisting major depressive episode with postpartum onset were compared with 10 mothers showing low depressive scores and no depressive symptoms on prospective follow-up. A distinctive gene expression signature was observed after delivery among mothers with an emergent PD, with a significant overabundance of transcripts showing a high-fold differential expression between groups, and correlating with depressive symptom severity among all mothers. Early expression signatures correctly classified the majority of PD patients and controls. Those developing persisting PD exhibit a relative downregulation of transcription after delivery, with differential immune activation, and decreased transcriptional engagement in cell proliferation, and DNA replication and repair processes. Our data provide initial evidence indicating that blood cells sampled shortly after delivery may harbor valuable prognostic information for identifying the onset of persisting PD. Some of the informative transcripts and pathways may be implicated in the differential vulnerability that underlies depression pathogenesis.
Sujet(s)
Dépression du postpartum/sang , Dépression du postpartum/physiopathologie , Régulation de l'expression des gènes/physiologie , Agranulocytes/métabolisme , Adulte , Études cas-témoins , Prolifération cellulaire , Dépression du postpartum/génétique , Femelle , Analyse de profil d'expression de gènes/méthodes , Gènes précoces/génétique , Gènes précoces/physiologie , Humains , Séquençage par oligonucléotides en batterie/méthodes , Échelles d'évaluation en psychiatrie , Facteurs tempsRÉSUMÉ
Schizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug x gene and drug x haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine- or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids.
Sujet(s)
Neuroleptiques/effets indésirables , Apolipoprotéine C-III/génétique , Apolipoprotéines A/génétique , Lipides/sang , Lipoprotein lipase/génétique , Polymorphisme de nucléotide simple , Schizophrénie/traitement médicamenteux , Adulte , Allèles , Apolipoprotéine A-V , Benzodiazépines/effets indésirables , Clozapine/effets indésirables , Études transversales , Femelle , Haplotypes , Humains , Mâle , Adulte d'âge moyen , Olanzapine , Schizophrénie/sang , Schizophrénie/génétiqueSujet(s)
Trouble déficitaire de l'attention avec hyperactivité/génétique , Transporteurs de la dopamine/génétique , Haplotypes/génétique , Répétitions minisatellites/génétique , Trouble déficitaire de l'attention avec hyperactivité/métabolisme , Enfant , Enfant d'âge préscolaire , Dopamine/métabolisme , Transporteurs de la dopamine/métabolisme , Prédisposition génétique à une maladie , Humains , Juif/génétique , Déséquilibre de liaison , PedigreeRÉSUMÉ
Trauma survivors show marked differences in the severity and persistence of post-traumatic stress disorder (PTSD) symptoms. Early symptoms subside in most, but persist as acute and chronic PTSD in a significant minority. The underlying molecular mechanisms or outcome predictors determining these differences are not known. Molecular markers for identifying any mental disorder are currently lacking. Gene expression profiling during the triggering and development of PTSD may be informative of its onset and course. We used oligonucleotide microarrays to measure peripheral blood mononuclear cell (PBMC) gene expression of trauma survivors at the emergency room and 4 months later. Gene expression signatures at both time points distinguished survivors who met DSM-IV diagnostic criteria for PTSD at 1 and 4 months, from those who met no PTSD criterion. Expression signatures at both time points correlated with the severity of each of the three PTSD symptom clusters assessed 4 months following exposure among all survivors. Results demonstrate a general reduction in PBMCs' expression of transcription activators among psychologically affected trauma survivors. Several differentiating genes were previously described as having a role in stress response. These findings provide initial evidence that peripheral gene expression signatures following trauma identify an evolving neuropsychiatric disorder and are informative of its key clinical features and outcome. Replications in larger samples, as well as studies focusing on specific markers within the signatures discovered, are warranted to confirm and extend the diagnostic utility and pathogenetic implications of our results.
Sujet(s)
Adaptation psychologique/physiologie , Analyse de profil d'expression de gènes , Agranulocytes/physiologie , Troubles de stress post-traumatique/génétique , Stress psychologique/génétique , Adolescent , Adulte , Études de suivi , Marqueurs génétiques/génétique , Humains , Événements de vie , Adulte d'âge moyen , Séquençage par oligonucléotides en batterie , Valeur prédictive des tests , Indice de gravité de la maladie , Troubles de stress post-traumatique/sang , Troubles de stress post-traumatique/psychologie , Survivants/psychologieRÉSUMÉ
BACKGROUND: Antipsychotic drugs are widely used for the treatment of psychosis, especially schizophrenia. Their long-term use can result at times in serious side-effects such as Tardive Dyskinesia (TD). Since over 80% of schizophrenia sufferers (lifetime prevalence 1%) receive long-term antipsychotic drug treatment, the extent of the problem is potentially large. Increasing age is the most consistently demonstrated risk factor for TD. AIMS: To assess effect of different clinical factors and demographic variables in India and Israel and sib pair concordance of Tardive Dyskinesia (TD) in India. SETTINGS AND DESIGN: The study was conducted simultaneously among Indian and Israeli subjects: ascertainment was family-based in India and hospital-based in Israel. METHODS AND MATERIAL: In India the instruments used were: Diagnostic Interview for Genetic Studies (DIGS), Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and Simpson Angus Scale (SAS). The last three instruments were also used in Israel. STATISTICAL ANALYSIS: Regression analysis and Pearson's correlation. RESULTS AND CONCLUSIONS: TD symptoms were present in 40.4% of 151 Israeli subjects and 28.7% of 334 Indian subjects. While age at onset and total scores on PANSS were significant predictors of TD in both the samples, lower scores on the Global Assessment of Functioning Scale (GAF), diagnostic sub-group and male gender were significant predictors among Indians. There was no concordance of TD symptoms among 33 affected sib-pairs from India.
Sujet(s)
Neuroleptiques/effets indésirables , Dyskinésie due aux médicaments/épidémiologie , Dyskinésie due aux médicaments/étiologie , Adulte , Femelle , Humains , Inde/épidémiologie , Israël/épidémiologie , Mâle , Tests neuropsychologiques , Échelles d'évaluation en psychiatrieRÉSUMÉ
Schizophrenia is characterized by thought disorders, hallucinations and delusions. Genetic studies have shown a high linkage at chromosome 6q16-21. Among the genes located in this region is the glutamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia. In this study, transmission of GRIK2 was evaluated in 356 schizophrenic patients from three different clinical centers. Whereas paternal transmission shows equilibrium, we observed maternal transmission disequilibrium of GRIK2 in the largest population (p=0.03), which was still significant when all populations were added (p=0.05). These results are similar to the maternal GRIK2 transmission disequilibrium previously reported for autism, and support the presence of a susceptibility gene for schizophrenia at 6q16.
Sujet(s)
Déséquilibre de liaison , Mères , Récepteurs kaïnate/génétique , Schizophrénie/génétique , Allèles , Études cas-témoins , Chromosomes humains de la paire 6 , Prédisposition aux maladies , Femelle , Génomique , Génotype , Humains , Mâle , Polymorphisme de nucléotide simple ,RÉSUMÉ
Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal side effect profile of atypical antipsychotic drugs. We evaluated candidate dopamine and serotonin genes for association with drug-induced TD. We examined three polymorphisms in the dopamine D2 receptor gene (DRD2), two sites in the 3' region of the dopamine transporter (DAT) gene, two sites in the promoter and coding region of the dopamine D4 (DRD4) receptor gene, as well as polymorphic sites in the serotonin 6 receptor gene, the serotonin transporter gene and the tryptophan hydroxylase gene, for association with TD susceptibility. Schizophrenic patients with (n=59) and without TD (n=63), matched for antipsychotic drug exposure and other relevant variables, were studied. No significant associations were found. Within the limitations imposed by the size of the clinical sample, these findings suggest that the above polymorphic loci do not contribute significantly to risk for TD. Further examination of loci that yielded positive results at a trend level and investigation of other candidate genetic loci coding for antipsychotic drug targets is warranted.
Sujet(s)
Dopamine/génétique , Dyskinésie due aux médicaments/génétique , Schizophrénie/génétique , Sérotonine/génétique , Adulte , Sujet âgé , Neuroleptiques/effets indésirables , Loi du khi-deux , Femelle , Fréquence d'allèle/génétique , Génotype , Humains , Mâle , Adulte d'âge moyen , Polymorphisme génétique/génétique , Schizophrénie/traitement médicamenteuxRÉSUMÉ
Schizophrenia is a complex neuropsychiatric disorder to which an as-yet-unknown number of genes contribute, interacting with each other and the environment. Linkage analyses have implicated several chromosomal regions as harboring schizophrenia susceptibility loci although rarely at levels commensurate with proposed thresholds for genome-wide significance. We systematically recruited Arab Israeli families multiply affected with schizophrenia from the catchment area of a Regional Mental Health Center. Clinical diagnoses were established by semistructured interviews and all other available sources of information under narrow, core and broad categories. Using 350 microsatellite markers, spaced at an average of 10.3 cM, we performed an autosomal scan in 155 subjects from 21 families. Linkage analysis employed affects only, multipoint, nonparametric (model-free) and also parametric (dominant and recessive) approaches. We detected significant evidence for a schizophrenia susceptibility gene at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P=0.000004) under the broad diagnostic category and a parametric LOD score of 3.33 (dominant model). Under the core diagnostic category the NPL was 4.29 (P=0.00001) and the LOD score 4.16 (dominant model). We also detected suggestive evidence for linkage at chromosome 10q24 under the broad diagnostic category (NPL 3.24, P=0.0008; heterogeneity LOD score, dominant model 2.65, alpha=0.82). Additionally, NPL scores >2.0 were observed at chromosome 2q37, 4p15-16, 7p22, 9q21-22 and 14q11.1-11.2. The linkage we detected at chromosome 6q23 fulfills the criteria for genome-wide significance and is located approximately midway between loci suggested by a previous significant report at chromosome 6q25 and findings located more centromerically at 6q21-22.
Sujet(s)
Arabes/génétique , Chromosomes humains de la paire 10 , Chromosomes humains de la paire 6 , Lod score , Schizophrénie/génétique , Santé de la famille , Prédisposition génétique à une maladie , Génome humain , Génotype , Humains , IsraëlRÉSUMÉ
Posttraumatic stress disorder (PTSD) is a chronic anxiety disorder that follows exposure to extreme events. A large twin study of Vietnam veterans had demonstrated a significant genetic contribution to chronic PTSD upon exposure to combat.(1,2) The underlying genes, however, have not been described. Given previous findings of abnormal dopamine (DA) function in PTSD, and given the putative effect of dopamine neurotransmission in shaping the responses to stress in animals, this study examined the association of the dopamine transporter (DAT) SLC6A3 3' variable number tandem repeat (VNTR) polymorphism with PTSD. The study evaluated 102 chronic PTSD patients and 104 carefully-documented trauma survivors (TS) who did not develop PTSD. Significant excess of 9 repeat allele was observed among PTSD patients (43% vs 30.5% in TS controls; chi(2) = 6.3, df = 1, P = 0.012). An excess of 9 repeat homozygous genotype was also observed in PTSD (20.43% in PTSD vs 9.47% in TS controls; chi(2) = 6.11, df = 2, P < 0.047). These findings suggest that genetically determined changes in dopaminergic reactivity may contribute to the occurrence of PTSD among trauma survivors.
Sujet(s)
Glycoprotéines membranaires , Protéines de transport membranaire/génétique , Protéines de tissu nerveux , Troubles de stress post-traumatique/génétique , Adulte , Chimie du cerveau/génétique , Transporteurs de la dopamine , Femelle , Fréquence d'allèle , Génotype , Humains , Mâle , Adulte d'âge moyenSujet(s)
Troubles de la motricité/génétique , Récepteur D2 de la dopamine/génétique , Récepteurs sérotoninergiques/génétique , Schizophrénie/génétique , Adulte , Facteurs âges , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladie chronique , Humains , Adulte d'âge moyen , Troubles de la motricité/étiologie , Récepteur de la sérotonine de type 5-HT2A , Récepteur de la sérotonine de type 5-HT2C , Récepteur D3 de la dopamine , Schizophrénie/complicationsRÉSUMÉ
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, where family data support substantial heritability.(1) To date, association studies focussed mainly on genes regulating dopaminergic neurotransmission.(2)Interleukin-1 (IL-1) activity in the brain has been implicated with differentiation of dopaminergic neurons(3,4) and modulation of central monoaminergic reactivity.(5) We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) gene variable number tandem repeat (VNTR) polymorphism,(6) in a sample of 86 children with DSM-IV ADHD and their parents. Transmission disequilibrium analysis showed increased transmission of the IL-1Ra 4-repeat allele (chi(2) = 4.07, P = 0.04) and decreased transmission of the 2-repeat allele (chi(2) = 4.59, P = 0.03) to affected children. The 4-repeat allele was associated with a significantly increased risk for ADHD (chi(2) = 4.46, df 1, P = 0.035, RR = 1.292, 95% CI 1.01-1.66). The IL-1Ra 2-repeat allele was associated with a significantly decreased risk for ADHD (chi(2) = 4.65, df 1, P = 0.03, RR = 0.763, 95% CI 0.59-0.98). If replicated, this finding may point to a role for brain cytokine activity in the etiopathogenesis of ADHD.
Sujet(s)
Trouble déficitaire de l'attention avec hyperactivité/génétique , Répétitions minisatellites , Sialoglycoprotéines/génétique , Adolescent , Adulte , Allèles , Enfant , Cytokines/physiologie , Femelle , Prédisposition génétique à une maladie , Humains , Antagoniste du récepteur à l'interleukine-1 , Israël , Déséquilibre de liaison , Mâle , RisqueRÉSUMÉ
Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.(1) Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs(2) and also in the action of mood stabilizing agents, particularly lithium carbonate.(3) Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain,(4) are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),(5) in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, chi(2) = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (chi(2) = 7.34, df 1, P = 0.006) and BP (chi(2) = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder.
Sujet(s)
Trouble bipolaire/génétique , Trouble dépressif/génétique , Prédisposition génétique à une maladie , Variation génétique , Polymorphisme génétique , Récepteurs sérotoninergiques/génétique , Substitution d'acide aminé , Cystéine , Ethnies , Europe/ethnologie , Femelle , Fréquence d'allèle , Liaison génétique , Humains , Israël , Méthode des moindres carrés , Fonctions de vraisemblance , Mâle , Récepteur de la sérotonine de type 5-HT2C , Valeurs de référence , Sérine ,RÉSUMÉ
Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.(1) Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.(2) We examined the association of three polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD susceptibility--T102C(3) and his452tyr(4) in the coding region and A-1438G(5) in the promoter--in matched schizophrenia patients with (n = 59, SCZ-TD-Y) and without TD (n = 62, SCZ-TD-N) and normal control subjects (n = 96). The T102C and the A-1438G polymorphisms are in complete linkage disequilibrium but not his452tyr. There was a significant excess of 102C and -1438G alleles (62.7%) in the SCZ-TD-Y patients compared to SCZ-TD-N patients (41.1%) and controls (45.9%; chi(2) = 12.8, df = 2, P = 0.002; SCZ-TD-Y vs SCZ-TD-N, chi(2) = 11.4, df = 1, P = 0.0008, OR 2.41, 95% CI 1.43-3.99) and of 102CC and -1438GG genotypes (SCZ-TD-Y 42.4%, SCZ-TD-N, 16.1%, controls 20.8%, chi(2) = 13.3, df = 4, P = 0.01). The 102CC and the -1438GG genotypes were associated with significantly higher AIMS trunk dyskinesia scores (F = 3.9; df = 2, 116; P = 0.02) and more incapacitation (F = 5.0; df = 2, 115; P = 0.006). The his452tyr polymorphism showed no association with TD. These findings suggest that the 5-HT2A receptor gene is significantly associated with susceptibility to TD in patients with chronic schizophrenia. Previously reported association of the T102C and A-1438G polymorphisms with schizophrenia(6) may reflect association of a sub-group of patients with a susceptibility to abnormal involuntary movements related to antipsychotic drug exposure.
Sujet(s)
Dyskinésie due aux médicaments/génétique , Récepteurs sérotoninergiques/génétique , Schizophrénie/génétique , Adulte , Neuroleptiques/effets indésirables , Maladie chronique , Femelle , Marqueurs génétiques , Humains , Mâle , Adulte d'âge moyen , Récepteur de la sérotonine de type 5-HT2A , Schizophrénie/traitement médicamenteuxRÉSUMÉ
Evidence from epidemiological studies and segregation analysis suggests oligo- or polygenic inheritance in schizophrenia. Since model independent methods are thought to be most appropriate for linkage analysis in complex disorders, we performed a genome-wide autosomal screen in 71 families from Germany and Israel containing 86 independent affected sib-pairs with parental genotype information for statistical analysis strictly identity by descent. We genotyped 305 individuals with 463 markers at an average distance of approximately 10 cM genome-wide, and 1-2 cM in candidate regions (5q, 6p, q, 8p, 10p, 18p, 22q). The highest multipoint LOD scores (ASPEX) were obtained on 6p (D6S260, LOD = 2.0; D6S274, LOD = 2.2, MHC region, LOD = 2.15) and on 10p (D10S1714, LOD = 2.1), followed by 5q (D5S2066, LOD = 1.36), 6q (D6S271, LOD = 1.12; D6S1613, LOD = 1.11), 1q (D1S2675, LOD = 1.04), and 18p (broad disease model: D18S1116, LOD = 1.0). One hundred and thirty-three additional family members were available for some of the families (extended families) and were genotyped for these regions. GENEHUNTER produced a maximum NPL of 3.3 (P = 0.001) for the MHC region and NPL of 3.13 (P = 0.0015) for the region on 10p. There is support for these regions by independent groups. In genome-wide TDT analysis (sTDT, implemented in ASPEX), no marker passed the significance level of 0.0001 given by multiple testing, but nominal significance values for D10S211 (P = 0.03) and for GOLF (P = 0.0032) support further the linkage results on 10p and 18p. Our survey of 22 chromosomes identified candidate regions which should be useful to screen for schizophrenia susceptibility genes.
Sujet(s)
Chromosomes humains de la paire 10 , Chromosomes humains de la paire 6 , Santé de la famille , Dépistage génétique/méthodes , Schizophrénie/génétique , Cartographie chromosomique , Prédisposition génétique à une maladie , Génome humain , Génotype , Humains , Déséquilibre de liaison , Famille nucléaire , Schizophrénie/diagnosticRÉSUMÉ
RATIONALE: Tardive dyskinesia (TD) is a longterm adverse effect of dopamine receptor blockers. The dopamine D3 receptor gene (DRD3) ser9gly polymorphism has been previously associated with susceptibility to TD. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extra-pyramidal effects profile of atypical antipsychotic drugs. OBJECTIVES: To examine the association of a functional polymorphism in the 5-HT2C receptor gene (HT2CR) with TD and the joint contribution of HT2CR and DRD3 to susceptibility. METHODS: Case control association analysis of allele and genotype frequencies among schizophrenia patients with (n=55) and without TD (n=60), matched for antipsychotic drug exposure and other relevant variables, and normal control subjects (n=97). Parametric analyses of the contribution of 5-HT2Cser and DRD3gly alleles to dyskinesia scores. RESULTS: We found a significant excess of 5-HT2Cser alleles in schizophrenia patients with TD (27.2%) compared to patients without TD (14.6%) and normal controls (14.2%; chi2=6.4, df 2, P=0.03) which was due to the female patients (chi2=8.6, df 2, P=0.01). Among the female TD patients there was an excess of cys-ser and ser-ser genotypes (chi2= 11.9, df 4, P=0.02). Analysis of covariance (ANCOVA), controlling for age at first antipsychotic treatment, revealed a significant effect of 5-HT2C genotype on orofacial dyskinesia (OFD) scores (F=3.47, df 2, P=.03). In a stepwise multiple regression analysis, 5-HT2C and DRD3 genotype (5-HT2Cser and DRD3gly allele carriage) respectively contributed 4.2% and 4.7% to the variance in OFD scores. CONCLUSIONS: These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.
Sujet(s)
Acathisie due aux médicaments/génétique , Récepteurs sérotoninergiques/génétique , Schizophrénie/génétique , Adolescent , Adulte , Sujet âgé , Acathisie due aux médicaments/étiologie , Allèles , Analyse de variance , Maladie chronique , Femelle , Fréquence d'allèle , Prédisposition génétique à une maladie , Génotype , Humains , Mâle , Adulte d'âge moyen , Polymorphisme génétique , Récepteur de la sérotonine de type 5-HT2C , Récepteur D2 de la dopamine/génétique , Récepteur D3 de la dopamine , Schizophrénie/complicationsRÉSUMÉ
In spite of substantial advances in the treatment of major depression by pharmacotherapy and other means, a significant number of depressed patients require hospitalization. In the context of the Jerusalem Collaborative Depression Project, possible precipitants of psychiatric hospitalization were sought in a cohort of patients (n = 107) who were admitted to hospitals in the Jerusalem area during a 14-month period because of a depressive episode. The patients fulfilled DSM III-R criteria for major depression, single or recurrent; bipolar 1 disorder, depressed or mixed; bipolar 2, depressed. The cohort encompassed more than two thirds of potential subjects admitted during this period with the ICD-9 equivalents of the specified diagnoses (as reported to the Israel Ministry of Health National Psychiatric Case Register) and were similar to the entire potential population in terms of their diagnostic breakdown. The patients underwent extensive socio-demographic and clinical evaluation that included detailed documentation of treatment received prior to hospitalization. Notwithstanding the absence of a comparison group of depressed patients who were not hospitalized, a number of potential precipitants were identified. These included older age (55.2% > 60 years, 20.6% > 70 years), immigration to Israel during the preceding 5 years (34.7%), concomitant physical illness (60%) which was associated with moderate to severe disability in 41% and poor quality of antidepressant pharmacotherapy prior to hospitalisation (only 24.3% received an adequate trial of antidepressant medication). Further evaluation of these and other potential factors could facilitate targeting of patient groups at particular risk for hospitalization and reduce the need for it.
Sujet(s)
Trouble bipolaire/rééducation et réadaptation , Trouble dépressif majeur/rééducation et réadaptation , Admission du patient , Adulte , Sujet âgé , Trouble bipolaire/diagnostic , Trouble bipolaire/psychologie , Études de cohortes , Trouble dépressif majeur/diagnostic , Trouble dépressif majeur/psychologie , État de santé , Hospitalisation , Hôpitaux psychiatriques , Humains , Israël , Adulte d'âge moyen , Projets pilotes , Échelles d'évaluation en psychiatrie , Études rétrospectives , Facteurs de risque , Indice de gravité de la maladieRÉSUMÉ
Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine substitution in the first exon of the gene encoding the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched patients with similar antipsychotic exposure but no TD and 117 normal controls. There was a difference in allele frequency that was of borderline significance (P = 0.055), due to an excess of the DRD3gly allele (allele 2) in the schizophrenia patients with TD. The difference in genotype distribution among the groups was highly significant (chi2 = 19.1, d.f. 4, P = 0.0008) due to an excess of the DRD3ser-gly genotype in the schizophrenia patients with TD. The difference between the schizophrenia patients with TD and the controls was highly significant (chi2 = 19.0, d.f. 2, P = 0.00007), even after correction for multiple testing, as was the difference between the combined group of schizophrenia patients and the controls (chi2 = 12.2, d.f. 2, P = 0.002). Comparing the schizophrenia patients with and without TD, genotypes containing the gly allele (DRD3ser-gly and DRD3gly-gly genotypes combined) were significantly associated with dyskinesia (OR = 2.62, 95% CI 1.18-5.59, P = 0.02). DRD3 genotype and age at first antipsychotic treatment contributed significantly to total score on the Abnormal Involuntary Movements Scale (AIMS). The contribution of DRD3 to the variance in AIMS total was 5.2% and the total proportion of the variance accounted for by these two variables together was 11.9%. These results support and extend the report by Steen et al (1997) of an association between DRD3 and TD in schizophrenia patients.
Sujet(s)
Dyskinésie due aux médicaments/étiologie , Dyskinésie due aux médicaments/génétique , Récepteur D2 de la dopamine/génétique , Schizophrénie/génétique , Schizophrénie/physiopathologie , Adulte , Neuroleptiques/usage thérapeutique , Femelle , Génotype , Glycine , Humains , Israël , Juif/génétique , Mâle , Adulte d'âge moyen , Récepteur D3 de la dopamine , Valeurs de référence , Schizophrénie/complications , SérineRÉSUMÉ
A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders, since it plays a role in modulating neuronal firing patterns by regulating the slow component of after hyperpolarisation. In addition, the gene contains a highly polymorphic trinucleotide sequence (CAG) within exon 1, which encodes a polyglutamine stretch. The possible contribution of unstable trinucleotide repeats to the development of psychiatric disorders has previously been discussed. Chandy et al reported an over-representation of alleles with higher repeat number in schizophrenics as compared to controls (P = 0.0035). In an attempt to replicate these findings, we have performed a family-based study with 193 offspring/parent combinations using a sample of 49 multiplex families (two or more affected siblings with parents) and a second sample of 83 simplex families (one affected offspring with parents). No evidence for the association of longer repeats with schizophrenia was obtained when each sample was tested separately or when both samples were combined and tested for transmission disequilibrium.
Sujet(s)
Déséquilibre de liaison , Neuropeptides/génétique , Canaux potassiques/génétique , Schizophrénie/génétique , Femelle , Dépistage génétique , Génotype , Humains , Mâle , Famille nucléaire , Réaction de polymérisation en chaîne , Valeurs de référence , Canaux potassiques calcium-dépendants de petite conductanceRÉSUMÉ
Severe disturbances of sleep architecture and circadian rhythms are common in traumatic brain injured patients; however, complete absence of the rapid eye movement sleep stage is very rare. We describe a brain injured patient with cognitive disturbances who developed severe alterations of sleep architecture, accompanied by paranoid and jealousy delusions. Following several trials with conventional antipsychotics his psychotic state stabilized but he continued to complain of insomnia and daytime fatigue. When treated with risperidone 2 mg/day, both his sleep and the delusional thoughts improved markedly and his daytime alertness increased. Severe deterioration of his support system brought about discontinuation of treatment with re-emergence of all symptoms.