RESUMEN
Social anxiety disorder (SAD) and panic disorder (PD) are prevalent anxiety disorders characterized by a complex interplay of genetic and environmental factors. Both disorders share overlapping features and often coexist, despite displaying distinct characteristics. Childhood life adversity, overall stressful life events, and genetic factors contribute to the development of these disorders. DNA methylation, an epigenetic modification, has been implicated in the pathogenesis of these diseases. In this study, we investigated whether whole-genome DNA methylation risk scores (MRSs) for SAD risk, severity of social anxiety, childhood life adversity, PD risk, and overall stressful life events were associated with SAD or PD caseâcontrol status. Preliminary epigenome-wide association studies (EWASs) for SAD risk, severity of social anxiety, and childhood life adversity were conducted in 66 SAD individuals and 77 healthy controls (HCs). Similarly, EWASs for PD risk and overall stressful life events were performed in 182 PD individuals and 81 HCs. MRSs were calculated from these EWASs. MRSs derived from the EWASs of SAD risk and severity of social anxiety were greater in PD patients than in HCs. Additionally, MRSs derived from the EWASs of overall stressful life events, particularly in PD individuals, were lower in SAD individuals than in HCs. In contrast, MRSs for childhood life adversity or PD risk were not significantly associated with PD or SAD caseâcontrol status. These findings highlight the epigenetic features shared in both disorders and the distinctive epigenetic features related to social avoidance in SAD patients, helping to elucidate the epigenetic basis of these disorders.
Asunto(s)
Experiencias Adversas de la Infancia , Metilación de ADN , Epigénesis Genética , Estudio de Asociación del Genoma Completo , Trastorno de Pánico , Fobia Social , Estrés Psicológico , Humanos , Trastorno de Pánico/genética , Masculino , Femenino , Adulto , Fobia Social/genética , Estrés Psicológico/genética , Estudios de Casos y Controles , Persona de Mediana Edad , Adulto JovenRESUMEN
Major depressive disorder (MDD) is a clinically and genetically heterogeneous disorder. To reduce heterogeneity, large-scale genome-wide association studies have recently identified genome-wide significant loci associated with seven MDD subtypes. However, it was unclear in which tissues the genes near those loci are specifically expressed. We investigated whether genes related to specific MDD subtypes would be preferably expressed in a specific tissue. At 14 novel subtype-specific loci related to seven MDD subtypes-(1) non-atypical-like features MDD, (2) early-onset MDD, (3) recurrent MDD, (4) MDD with suicidal thoughts, (5) MDD without suicidal thoughts, (6) MDD with moderate impairment, and (7) postpartum depression, we investigated whether 22 genome-wide significant genetic variant-mapped genes were tissue-specifically expressed in brain, female reproductive, male specific, cardiovascular, gastrointestinal, or urinary tissues in the Genotype-Tissue Expression (GTEx) subjects (n ≤ 948). To confirm the tissue-specific expression in the GTEx, we used independent Human Protein Atlas (HPA) RNA-seq subjects (n ≤ 95). Of 22 genes, nine and five genes were tissue-specifically expressed in brain and female reproductive tissues, respectively (p < 2.27 × 10-3). RTN1, ERBB4, and AMIGO1 related to early-onset MDD, recurrent MDD, or MDD with suicidal thoughts were highly expressed in brain tissues (d = 1.19-2.71), while OAS1, LRRC9, DHRS7, PSMA5, SYPL2, and GULP1 related to non-atypical-like features MDD, early-onset MDD, MDD with suicidal thoughts, or postpartum depression were expressed at low levels in brain tissues (d = -0.17--1.48). DFNA5, CTBP2, PCNX4, SDCCAG8, and GULP1, which are related to early-onset MDD, MDD with moderate impairment, or postpartum depression, were highly expressed in female reproductive tissues (d = 0.80-2.08). Brain and female reproductive tissue-specific expression was confirmed in the HPA RNA-seq subjects. Our findings suggest that brain and female reproductive tissue-specific expression might contribute to the pathogenesis of MDD subtypes.
Asunto(s)
Trastorno Depresivo Mayor , Estudio de Asociación del Genoma Completo , Humanos , Trastorno Depresivo Mayor/genética , Femenino , Masculino , Adulto , Encéfalo/metabolismo , Expresión Génica , Especificidad de Órganos , Ideación Suicida , Persona de Mediana Edad , Depresión Posparto/genéticaRESUMEN
BACKGROUND: Genetic and environmental factors contribute to the pathogenesis of schizophrenia (SZ) and bipolar disorder (BD). Among genetic risk groups stratified by combinations of Polygenic Risk Score (PRS) deciles for SZ, BD and SZ versus BD, genetic SZ risk groups had high SZ risk and prominent cognitive impairments. Furthermore, epigenetic alterations are implicated in these disorders. However, it was unclear whether DNA Methylation Risk Scores (MRSs) for SZ risk derived from blood and brain tissues were associated with SZ risk, particularly the PRS-stratified genetic SZ risk group. METHODS: Epigenome-wide association studies (EWASs) of SZ risk in whole blood were preliminarily conducted between 66 SZ patients and 30 healthy controls (HCs) and among genetic risk groups (individuals with low genetic risk for SZ and BD in HCs (n=30) and in SZ patients (n=11), genetic BD risk in SZ patients (n=25) and genetic SZ risk in SZ patients (n=30)) stratified by combinations of PRSs for SZ, BD and SZ versus BD. Next, differences in MRSs based on independent EWASs of SZ risk in whole blood, postmortem frontal cortex (FC) and superior temporal gyrus (STG) were investigated among our caseâcontrol and PRS-stratified genetic risk status groups. RESULTS: Among caseâcontrol and genetic risk status groups, 33 and 351 genome-wide significant differentially methylated positions (DMPs) associated with SZ were identified, respectively, many of which were hypermethylated. Compared with the low genetic risk in HCs group, the genetic SZ risk in SZ group had 39 genome-wide significant DMPs, while the genetic BD risk in SZ group had only six genome-wide significant DMPs. The MRSs for SZ risk derived from whole blood, FC and STG were higher in our SZ patients than in HCs in whole blood and were particularly higher in the genetic SZ risk in SZ group than in the low genetic risk in HCs and genetic BD risk in SZ groups. Conversely, the MRSs for SZ risk based on our whole-blood EWASs among genetic risk groups were also associated with SZ in the FC and STG. There were no correlations between the MRSs and PRSs. CONCLUSIONS: These findings suggest that the MRS is a potential genetic marker in understanding SZ, particularly in patients with a genetic SZ risk.
Asunto(s)
Trastorno Bipolar , Esquizofrenia , Humanos , Esquizofrenia/genética , Trastorno Bipolar/genética , Metilación de ADN/genética , Puntuación de Riesgo Genético , Factores de Riesgo , Lóbulo FrontalRESUMEN
BACKGROUND: Suicide attempts are a moderately heritable trait, and genetic correlations with psychiatric and related intermediate phenotypes have been reported. However, as several mental disorders as well as major depressive disorder (MDD) are strongly associated with suicide attempts, these genetic correlations could be mediated by psychiatric disorders. Here, we investigated genetic correlations of suicide attempts with psychiatric and related intermediate phenotypes, with and without adjusting for mental disorders. METHODS: To investigate the genetic correlations, we utilized large-scale genome-wide association study summary statistics for suicide attempts (with and without adjusting for mental disorders), nine psychiatric disorders, and 15 intermediate phenotypes. RESULTS: Without adjusting for mental disorders, suicide attempts had significant positive genetic correlations with risks of attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, MDD, anxiety disorders and posttraumatic stress disorder; higher risk tolerance; earlier age at first sexual intercourse, at first birth and at menopause; higher parity; lower childhood IQ, educational attainment and cognitive ability; and lower smoking cessation. After adjusting for mental disorders, suicide attempts had significant positive genetic correlations with the risk of MDD; earlier age at first sexual intercourse, at first birth and at menopause; and lower educational attainment. After adjusting for mental disorders, most of the genetic correlations with psychiatric disorders were decreased, while several genetic correlations with intermediate phenotypes were increased. CONCLUSIONS: These findings highlight the importance of considering mental disorders in the analysis of genetic correlations related to suicide attempts and suggest that susceptibility to MDD, reproductive behaviors, and lower educational levels share a genetic basis with suicide attempts after adjusting for mental disorders.
Asunto(s)
Trastorno Depresivo Mayor , Trastornos Mentales , Trastornos por Estrés Postraumático , Femenino , Humanos , Niño , Intento de Suicidio , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/psicología , Estudio de Asociación del Genoma Completo , Trastornos Mentales/epidemiología , Trastornos Mentales/genética , Trastornos Mentales/psicología , Fenotipo , Factores de RiesgoRESUMEN
Adjustment disorder has three main subtypes: adjustment disorder with depressed mood, adjustment disorder with anxiety, and adjustment disorder with disturbance of conduct. The disorder is moderately heritable and has lifetime comorbidities with major depressive disorder (MDD), anxiety disorders, or risk-tolerant personality. However, it remains unclear whether the degrees of genetic correlations between adjustment disorder and other psychiatric disorders and intermediate phenotypes are similar or different to those between MDD, anxiety disorders or risk-tolerant personality and these other psychiatric disorders and intermediate phenotypes. To compare patterns of genetic correlations, we utilized large-scale genome-wide association study summary statistics for adjustment disorder-related disorders and personality trait, eleven other psychiatric disorders and fifteen intermediate phenotypes. Adjustment disorder had highly positive genetic correlations with MDD, anxiety disorders, and risk-tolerant personality. Among other psychiatric disorders, adjustment disorder, MDD, anxiety disorders and risk-tolerant personality were positively correlated with risks for schizophrenia (SCZ), bipolar disorder (BD), SCZ + BD, attention-deficit/hyperactivity disorder, and cross disorders. In contrast, adjustment disorder was not significantly correlated with risks for obsessive-compulsive disorder, Tourette syndrome, or posttraumatic stress disorder despite significant genetic correlations of MDD or anxiety disorders with these disorders. Among intermediate phenotypes, adjustment disorder, MDD, anxiety disorders, and risk-tolerant personality commonly had a younger age at first sexual intercourse, first birth, and menopause, lower cognitive ability, and higher rate of smoking initiation. Adjustment disorder was not genetically correlated with extraversion, although the related disorder and personality were correlated with extraversion. Only adjustment disorder was correlated with a higher smoking quantity. These findings suggest that adjustment disorder could share a genetic etiology with MDD, anxiety disorders and risk-tolerant personality trait, as well as have a disorder-specific genetic etiology.
Asunto(s)
Trastorno Depresivo Mayor , Femenino , Humanos , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/psicología , Trastornos de Adaptación , Estudio de Asociación del Genoma Completo , Depresión , Ansiedad , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/genética , Personalidad/genéticaRESUMEN
BACKGROUND: Bipolar disorder (BD) and schizophrenia (SZ) are complex psychotic disorders (PSY), with both environmental and genetic factors including possible maternal inheritance playing a role. Some studies have investigated whether genetic variants in the mitochondrial chromosome are associated with BD and SZ. However, the genetic variants identified as being associated are not identical among studies, and the participants were limited to individuals of European ancestry. Here, we investigate associations of genome-wide genetic variants in the mitochondrial chromosome with BD, SZ, and PSY in a Japanese population. METHODS: After performing quality control for individuals and genetic variants, we investigated whether mitochondrial genetic variants [minor allele frequency (MAF) > 0.01, n = 45 variants) are associated with BD, SZ, and PSY in 420 Japanese individuals consisting of patients with BD (n = 51), patients with SZ (n = 172), and healthy controls (HCs, n = 197). RESULTS: Of mitochondrial genetic variants, three (rs200478835, rs200044200 and rs28359178 on or near NADH dehydrogenase) and one (rs200478835) were significantly associated with BD and PSY, respectively, even after correcting for multiple comparisons (PGC=0.045-4.9 × 10- 3). In particular, individuals with the minor G-allele of rs200044200, a missense variant, were only observed among patients with BD (MAF = 0.059) but not HCs (MAF = 0) (odds ratio=∞). Three patients commonly had neuropsychiatric family histories. CONCLUSIONS: We suggest that mitochondrial genetic variants in NADH dehydrogenase-related genes may contribute to the pathogenesis of BD and PSY in the Japanese population through dysfunction of energy production.
Asunto(s)
Trastorno Autístico , Trastornos Mentales , Trastorno de la Personalidad Esquizotípica , Humanos , Trastorno Autístico/psicología , Universidades , Trastorno de la Personalidad Esquizotípica/diagnóstico , Trastorno de la Personalidad Esquizotípica/epidemiología , Trastorno de la Personalidad Esquizotípica/psicología , Personalidad , Inteligencia Emocional , Estudiantes/psicologíaRESUMEN
Patients with schizophrenia (SZ) display moderate reductions in brainstem volumes, including the midbrain, pons, superior cerebellar peduncle, and medulla oblongata. Here, we investigated alterations in brainstem volumes between SZ patients and healthy controls (HCs) stratified by sex. T1-weighted MRI brain scans were processed with FreeSurfer v6.0 in 156 SZ patients (61 males/95 females) and 205 HCs (133/72). Of the brainstem structures, pons volumes were significantly reduced, particularly in male SZ patients. The decreased pons volumes were correlated with lower levels of education but not duration of illness in male patients. These findings suggest that the reduction in pons volume in male patients might be occurred before or around the onset of the disorder.
RESUMEN
OBJECTIVE: Olfactory impairments, including identification, have been reported in patients with schizophrenia, while few studies have examined the olfactory function of unaffected first-degree relatives of patients with schizophrenia, and the sample sizes of first-degree relatives were relatively small. Here, we investigated olfactory identification ability among patients with schizophrenia, first-degree relatives and healthy controls (HCs) using relatively large sample sizes at a single institute. METHODS: To assess olfactory identification ability, the open essence odorant identification test was administered to 172 schizophrenia patients, 75 first-degree relatives and 158 healthy controls. Differences in olfactory identification and correlations between olfactory ability and clinical variables were examined among these participants. RESULTS: We found a significant difference in olfactory identification ability among the diagnostic groups (p = 7.65 × 10-16). Schizophrenia patients displayed lower olfactory identification ability than first-degree relatives (Cohen's d = -0.57, p = 3.13 × 10-6) and healthy controls (d = -1.00, p = 2.19 × 10-16). Furthermore, first-degree relatives had lower olfactory identification ability than healthy controls (d = -0.29, p = 0.039). Olfactory identification ability moderately and negatively correlated with the duration of illness (r = -0.41, p = 1.88 × 10-8) and negative symptoms (r = -0.28, p = 1.99 × 10-4) in schizophrenia patients, although the correlation with the duration of illness was affected by aging (r = -0.24). CONCLUSIONS: Our results demonstrated that schizophrenia patients have impaired olfactory identification ability compared with first-degree relatives and healthy controls, and the impaired olfactory identification ability of first-degree relatives was intermediate between those in schizophrenia patients and healthy controls. Olfactory identification ability was relatively independent of clinical variables. Therefore, olfactory identification ability might be an intermediate phenotype for schizophrenia.
Asunto(s)
Trastornos del Olfato , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico , Voluntarios Sanos , Familia , Olfato/genética , Trastornos del Olfato/diagnóstico , Trastornos del Olfato/genéticaRESUMEN
BACKGROUND: Individuals with schizophrenia (SCZ) and bipolar disorder (BD) display cognitive impairments, but the impairments in those with SCZ are more prominent, supported by genetic overlap between SCZ and cognitive impairments. However, it remains unclear whether cognitive performances differ between individuals at high and low genetic risks for SCZ or BD. METHODS: Using the latest Psychiatric Genomics Consortium (PGC) data, we calculated PGC3 SCZ-, PGC3 BD-, and SCZ v. BD polygenic risk scores (PRSs) in 173 SCZ patients, 70 unaffected first-degree relatives (FRs) and 196 healthy controls (HCs). Based on combinations of three PRS deciles, individuals in the genetic SCZ, genetic BD and low genetic risk groups were extracted. Cognitive performance was assessed by the Brief Assessment of Cognition in Schizophrenia. RESULTS: SCZ-, BD-, SCZ v. BD-PRSs were associated with case-control status (R2 = 0.020-0.061), and SCZ-PRS was associated with relative-control status (R2 = 0.023). Furthermore, individuals in the highest decile for SCZ PRSs had elevated BD-PRSs [odds ratio (OR) = 6.33] and SCZ v. BD-PRSs (OR = 1.86) compared with those in the lowest decile. Of the three genetic risk groups, the low genetic risk group contained more HCs, whereas the genetic BD and SCZ groups contained more SCZ patients (p < 0.05). SCZ patients had widespread cognitive impairments, and FRs had cognitive impairments that were between those of SCZ patients and HCs (p < 0.05). Cognitive differences between HCs in the low genetic risk group and SCZ patients in the genetic BD or genetic SCZ groups were more prominent (Cohen's d > -0.20) than those between HCs and SCZ patients in the no genetic risk group. Furthermore, SCZ patients in the genetic SCZ group displayed lower scores in verbal fluency and attention than those in the genetic BD group (d > -0.20). CONCLUSIONS: Our findings suggest that cognitive impairments in SCZ are partially mediated through genetic loadings for SCZ but not BD.
Asunto(s)
Trastorno Bipolar , Disfunción Cognitiva , Esquizofrenia , Humanos , Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Esquizofrenia/genética , Factores de Riesgo , Disfunción Cognitiva/genética , Cognición , Herencia Multifactorial , Predisposición Genética a la EnfermedadRESUMEN
Reproductive behaviors are associated with risks for psychiatric disorders. Reproductive phenotypes are moderately heritable and have genetic overlaps with risks for psychiatric disorders. However, the genetic and causal relationships between anxiety-related disorders or specific anxiety disorders and reproductive phenotypes remain unknown. We utilized large-scale genome-wide association study (GWAS) results (n = 9537-542,901) for five reproductive phenotypes [age at menarche, age at first sexual intercourse (AFS), age at first birth (AFB), number of children ever born (NEB), and age at menopause] and five anxiety-related disorders [panic disorder, anxiety disorders from the ANGST and the UK biobank (UKBB), posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD)]. To assess genetic correlations and causal associations, linkage disequilibrium score regression and Mendelian randomization analyses, respectively, were performed. We found that AFS and AFB were negatively correlated with anxiety disorders ANGST (AFS: rg ± SE = -0.28 ± 0.08, p = 6.00 × 10-4; AFB: -0.45 ± 0.11, p = 3.26 × 10-5), anxiety disorders UKBB (AFS: -0.18 ± 0.03, p = 9.64 × 10-9; AFB; -0.25 ± 0.03, p = 2.90 × 10-13) and PTSD (AFS: -0.42 ± 0.12, p = 4.00 × 10-4; AFB: -0.44 ± 0.12, p = 2.00 × 10-4) and positively correlated with OCD (AFS: 0.25 ± 0.05, p = 2.46 × 10-6; AFB: 0.25 ± 0.05, p = 3.92 × 10-7). Conversely, NEB was negatively correlated with OCD (-0.28 ± 0.08, p = 6.00 × 10-4). We revealed bidirectional effects between earlier AFS and AFB and anxiety disorders (odds ratios: ORearlier AFSâAnxiety = 1.64, p = 2.27 × 10-8; ORearlier AFBâAnxiety = 1.15, p = 2.28 × 10-3; ORAnxietyâearlier AFS = 1.02, p = 6.62 × 10-8; ORAnxietyâearlier AFB = 1.08, p = 1.60 × 10-4). In contrast, we observed unidirectional effects of later AFS and AFB on OCD (ORlater AFSâOCD = 2.18, p = 2.16 × 10-6; ORlater AFBâOCD = 1.22, p = 0.016). We suggest that those who have earlier sexual debut and childbirth are prone to risk for anxiety disorders and vice versa, while those who have later sexual debut and childbirth are genetically prone to risk for OCD. Our findings further support revising the diagnostic criteria (DSM-5) such that OCD is independent from anxiety disorders.
Asunto(s)
Estudio de Asociación del Genoma Completo , Trastorno Obsesivo Compulsivo , Femenino , Humanos , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/psicología , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/psicología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Ansiedad/genéticaRESUMEN
Cigarette smoking is highly prevalent among patients with bipolar disorder (BD). Structural brain abnormalities related to smoking behavior and BD risk are indicated by magnetic resonance imaging (MRI) studies. However, cortical alterations common to smoking behavior and BD remain unclear. Our purpose was to identify common cortical alterations between smoking behavior and BD. 3T MRI-based indices of cortical thickness and surface area using FreeSurfer were acquired from 166 healthy control (HC) nonsmokers, 39 HC smokers, 33 BD nonsmokers, and 18 BD smokers. A stepwise discriminant-function analysis (DFA) with cortical structures as predictors was performed to classify BD patients into nonsmokers and smokers. Next, DFAs with the selected structures as predictors were performed to discriminate smoking status or diagnostic status. Differences in the selected features among the four groups were examined. The first DFA showed that six brain features discriminated between nonsmokers and smokers among BD patients. The six brain features related to BD smoking status also discriminated between HCs and BD patients and HC nonsmokers and BD smokers. Among the six features, left insular thickness showed a negative additive effect of smoking status and BD diagnosis. Our findings suggest the common neurobiological involvement of insular thickness in smoking behavior and BDrisk.
Asunto(s)
Trastorno Bipolar , Encefalopatías , Trastorno Bipolar/diagnóstico por imagen , Encéfalo/patología , Encefalopatías/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Análisis Discriminante , Humanos , Imagen por Resonancia Magnética/métodos , FumarRESUMEN
Schizophrenia and bipolar disorder display clinical similarities and dissimilarities. We investigated whether the genetic factor differentiating schizophrenia from bipolar disorder is genetically associated with cognitive phenotypes and hippocampal volumes. We revealed genetic overlaps of the genetic differentiating factor with low general cognitive ability, low childhood IQ, low educational attainment and reduced hippocampal volumes. The genetic correlations with low general cognitive ability and reduced hippocampal volumes were associated with risk of schizophrenia, whereas the genetic correlations with high childhood IQ and educational attainment were associated with risks of bipolar disorder. These findings suggest these disorders have disorder-specific genetic factors related to clinical phenotypes.
RESUMEN
Blonanserin is a second-generation antipsychotic for the treatment of schizophrenia. Blonanserin has two different routes of administration: oral tablets/powder and transdermal patches. The aim of this study was to investigate as a post-hoc analysis of an original study whether switching from blonanserin tablets/powders to transdermal patches would reduce extrapyramidal symptoms (EPS) and/or the dose of antiparkinsonian drugs for the stabilization of blood pharmacokinetics in patients with schizophrenia. Patients with schizophrenia (n = 155) were enrolled in either cohort 1 or 2. In cohort 1 (n = 97), patients received 40-80 mg/day blonanserin transdermal patches for one year after taking 8-16 mg/day blonanserin tablets for 6 weeks, and the dose of patches was determined based on the dose of the tablets. In cohort 2 (n = 58), all patients started with 40 mg/day blonanserin patches and then received 40-80 mg/day for a year after taking blonanserin tablets/powders. Changes from the start of transdermal patch treatment in EPS and the dose of antiparkinsonian drugs at 3, 6, and 12 months were assessed using the Drug-Induced EPS Scale (DIEPSS) and biperiden equivalents of total antiparkinsonian drugs (BPD-eq), respectively. Among 155 patients, only four patients in cohort 1 discontinued owing to EPS during a patch period. Significant improvements from the start of patch treatment in the DIEPSS total score at any point were observed (mean change±SD): -0.44 ± 1.50 (p = 0.013), -0.07 ± 1.78 (p = 0.73), and - 0.14 ± 1.37 (p = 0.44) in cohort 1 and - 0.16 ± 1.32 (p = 0.40), -0.74 ± 1.92 (p = 0.020), and - 0.81 ± 2.22 (p = 0.047) in cohort 2 at 3, 6, and 12 months, respectively. In contrast, there were no significant changes from the start of patch treatment in BPD-eq at any month (p > 0.05). Transdermal patches of blonanserin are a more effective route of administration to diminish EPS than oral tablets/powder.
Asunto(s)
Discinesias/prevención & control , Piperazinas , Piperidinas , Polvos , Esquizofrenia/tratamiento farmacológico , Comprimidos , Parche Transdérmico , Administración Oral , Adulto , Antiparkinsonianos , Antipsicóticos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/uso terapéuticoRESUMEN
BACKGROUND: Intelligence is inversely associated with schizophrenia (SCZ) and bipolar disorder (BD); it remains unclear whether low intelligence is a cause or consequence. We investigated causal associations of intelligence with SCZ or BD risk and a shared risk between SCZ and BD and SCZ-specific risk. METHODS: To estimate putative causal associations, we performed multi-single nucleotide polymorphism (SNP) Mendelian randomization (MR) using generalized summary-data-based MR (GSMR). Summary-level datasets from five GWASs (intelligence, SCZ vs. control [CON], BD vs. CON, SCZ + BD vs. CON, and SCZ vs. BD; sample sizes of up to 269,867) were utilized. RESULTS: A strong bidirectional association between risks for SCZ and BD was observed (odds ratio; ORSCZ â BD = 1.47, p = 2.89 × 10-41, ORBD â SCZ = 1.44, p = 1.85 × 10-52). Low intelligence was bidirectionally associated with a high risk for SCZ, with a stronger effect of intelligence on SCZ risk (ORlower intelligence â SCZ = 1.62, p = 3.23 × 10-14) than the reverse (ORSCZ â lower intelligence = 1.06, p = 3.70 × 10-23). Furthermore, low intelligence affected a shared risk between SCZ and BD (OR lower intelligence â SCZ + BD = 1.23, p = 3.41 × 10-5) and SCZ-specific risk (ORlower intelligence â SCZvsBD = 1.64, p = 9.72 × 10-10); the shared risk (ORSCZ + BD â lower intelligence = 1.04, p = 3.09 × 10-14) but not SCZ-specific risk (ORSCZvsBD â lower intelligence = 1.00, p = 0.88) weakly affected low intelligence. Conversely, there was no significant causal association between intelligence and BD risk (p > 0.05). CONCLUSIONS: These findings support observational studies showing that patients with SCZ display impairment in premorbid intelligence and intelligence decline. Moreover, a shared factor between SCZ and BD might contribute to impairment in premorbid intelligence and intelligence decline but SCZ-specific factors might be affected by impairment in premorbid intelligence. We suggest that patients with these genetic factors should be categorized as having a cognitive disorder SCZ or BD subtype.
Asunto(s)
Trastorno Bipolar , Esquizofrenia , Trastorno Bipolar/genética , Estudio de Asociación del Genoma Completo , Humanos , Inteligencia/genética , Análisis de la Aleatorización Mendeliana , Esquizofrenia/genéticaRESUMEN
PURPOSE: The goal of this study was to evaluate the safety and effectiveness of lurasidone among patients with schizophrenia in a 12-week open-label extension study. PATIENTS AND METHODS: Patients who completed a 6-week, double-blind, placebo-controlled study were enrolled in a 12-week open-label extension study with flexible dosing of lurasidone at 40 or 80 mg/day. Safety assessments included adverse events, vital signs, laboratory tests, and electrocardiogram (ECG) parameters. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score, Clinical Global Impression-Severity Scale (CGI-S), Calgary Depression Scale for Schizophrenia (CDSS) and quality of life measure. RESULTS: A total of 289 patients were enrolled in the open-label extension study. Rates of treatment-emergent adverse events (TEAEs) were low; akathisia was the most common TEAE with an incidence of 6.6%. There were 54 patients (18.7%) who discontinued the extension study, with 17 (5.9%) discontinuing due to adverse events. Minimal or no effects of lurasidone on weight, body mass index, metabolic parameters, prolactin, and ECG parameters were evident. There was continued improvement to week 12 in PANSS and CGI-S scores beyond the initial gains made during the prior 6-week double-blind study. Non-responders to lurasidone 40 mg/day in the prior 6-week study showed a mean (standard deviation) improvement from open-label baseline of 10.7 (13.8) points on the PANSS total score after lurasidone dose was increased to a modal dose of 80 mg/day during the extension study. Changes from double-blind baseline in CDSS and quality of life were maintained in the extension study. CONCLUSION: Treatment with lurasidone 40 or 80 mg once daily (flexibly dosed) continued to be well tolerated with patients demonstrating further improvement in symptoms over the course of a 12-week open-label extension study in patients with schizophrenia.
RESUMEN
BACKGROUND: Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with impaired intelligence that predicts poor functional outcomes. However, little is known regarding the extent and severity of intelligence decline, that is, decreased present intelligence quotient (IQ) relative to premorbid levels, across psychiatric disorders and which clinical characteristics affect the decline. METHODS: Premorbid IQ, present IQ, and intelligence decline were compared across patients with MDD (n = 45), BD (n = 30), and SCZ (n = 139), and healthy controls (HCs; n = 135). Furthermore, we investigated which factors contribute to the intelligence decline in each diagnostic group. RESULTS: Significant differences were observed in premorbid IQ, present IQ, and intelligence decline across the diagnostic groups. Patients with each psychiatric disorder displayed lower premorbid and present IQ and more intelligence decline than HCs. Patients with SCZ displayed lower premorbid and present IQ and more intelligence decline than patients with MDD and BD, while there were no significant differences between patients with MDD and BD. When patients with BD were divided based on bipolar I disorder (BD-I) and bipolar II disorder (BD-II), degrees of intelligence decline were similar between MDD and BD-II and between BD-I and SCZ. Lower educational attainment was correlated with a greater degree of intelligence decline in patients with SCZ and BD but not MDD. CONCLUSIONS: These findings confirm that although all psychiatric disorders display intelligence decline, the severity of intelligence decline differs across psychiatric disorders (SCZ, BD-I > BD-II, MDD > HCs). Higher educational attainment as cognitive reserve contributes to protection against intelligence decline in BD and SCZ.
RESUMEN
Sensory processing is disrupted in several psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. In this review, we focus on the electrophysiological auditory steady-state response (ASSR) driven by high-frequency stimulus trains as an index for disease-associated sensory processing deficits. The ASSR amplitude is suppressed within the gamma band (≥30 Hz) among these patients, suggesting an imbalance between GABAergic and N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission. The reduced power and synchronization of the 40-Hz ASSR are robust in patients with schizophrenia. In recent years, similar ASSR deficits at gamma frequencies have also been reported in patients with bipolar disorder and autism spectrum disorder. We summarize ASSR abnormalities in each of these psychiatric disorders and suggest that the observed commonalities reflect shared pathophysiological mechanisms. We reviewed studies on phase resetting in which a salient sensory stimulus affects ASSR. Phase resetting induces the reduction of both the amplitude and phase of ASSR. Moreover, phase resetting is also affected by rare auditory stimulus patterns or superimposed stimuli of other modalities. Thus, sensory memory and multisensory integration can be investigated using phase resetting of ASSR. Here, we propose that ASSR amplitude, phase, and resetting responses are sensitive indices for investigating sensory processing dysfunction in psychiatric disorders.
RESUMEN
BACKGROUND: Impairments in intelligence are more severe in patients with schizophrenia (SCZ) than in patients with bipolar disorder (BD) despite clinical and genetic similarities between the disorders. Genetic loci differentiating SCZ from BD, that is, SCZ-specific risk, have been identified. Polygenetic [risk] scores (PGSs) for SCZ-specific risk are higher in SCZ patients than in healthy controls (HCs). However, the influence of genetic risk on impaired intelligence is poorly understood. Here, we investigated whether SCZ-specific risk could predict impairments in intelligence in SCZ patients and HCs. METHODS: Large-scale genome-wide association study datasets related to SCZ vs BD, childhood intelligence (CHI), and adulthood intelligence (n = 12 441-282â 014) were utilized to compute PGSs. PGSs derived from the genome-wide association studies were calculated for 130 patients with SCZ and 146 HCs. Premorbid and current intelligence and the decline were measured in SCZ patients and HCs. Correlations between PGSs and intelligence functions were investigated. RESULTS: High PGSs for SCZ-specific risk were correlated with low premorbid intelligence in SCZ patients and HCs (ß = -0.17, P = 4.12 × 10-3). The correlation was still significant after adjusting for diagnostic status (ß = -0.13, P = .024). There were no significant correlations between PGSs for SCZ-specific risk and current intelligence or intelligence decline (Pâ >â .05). PGSs for CHI were lower in SCZ patients than in HCs (R2 = 0.025, P = .025), while the PGSs for CHI were not significantly correlated with premorbid and current intelligence, the decline, or the PGSs for SCZ-specific risk (Pâ >â .05). CONCLUSIONS: These findings suggest that genetic factors differentiating SCZ from BD might affect the pathogenesis of SCZ and/or pathological differences between SCZ and BD via the impairment of premorbid intelligence, that is, crystallized intelligence, while genetic factors for CHI might affect the pathogenesis of SCZ but not via impairments in intelligence.
Asunto(s)
Trastorno Bipolar , Disfunción Cognitiva , Predisposición Genética a la Enfermedad , Inteligencia/fisiología , Esquizofrenia , Adulto , Trastorno Bipolar/complicaciones , Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatología , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Herencia Multifactorial , Esquizofrenia/complicaciones , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Adulto JovenRESUMEN
The thermal behavior of ash components in two bituminous coal samples [Upper Freeport (the "UF") and Illinois #6 (the "IL")] was investigated under air and argon atmospheres in the temperature range of 800-1200 °C using thermal gravimetric-differential thermal analysis, X-ray diffraction transmission electron microscopy (TEM), and TEM-energy dispersive X-ray spectrometry measurements. The UF treated under air formed the needle-like crystals which were assumed to be mullite-related substances formed by transformation of andalusite, because the crystals are mainly composed of SiO2 and Al2O3. In contrast to the UF, the IL did not generate such crystals; however, when the IL was treated under air after carbonization under Ar, crystals appeared. The composition of the UF with an Al/Si ratio higher than that of the IL favored the formation of mullite-related substances, while the presence of lime in the IL inhibited the formation of mullite-related substances. Oldhamite was formed by the reaction of lime with sulfur at the carbonization of the IL under Ar and remained even at the successive air treatment. As lime was consumed, the formation of mullite-related substances was ceased to be inhibited under air after Ar treatment.