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Baby schema features are a specific set of physical features-including chubby cheeks, large, low-set eyes, and a large, round head-that have evolutionary adaptive value in their ability to trigger nurturant care. In this study among nulliparous women (N = 81; M age = 23.60, SD = 0.44), we examined how sensitivity to these baby schema features differs based on individual variations in nurturant care motivation and oxytocin system gene methylation. We integrated subjective ratings with measures of facial expressions and electroencephalography (EEG) in response to infant faces that were manipulated to contain more or less pronounced baby schema features. Linear mixed effects analyses demonstrated that infants with more pronounced baby schema features were rated as cuter and participants indicated greater motivation to take care of them. Furthermore, infants with more pronounced baby schema features elicited stronger smiling responses and enhanced P2 and LPP amplitudes compared to infants with less pronounced baby schema features. Importantly, individual differences significantly predicted baby schema effects. Specifically, women with low OXTR methylation and high nurturance motivation showed enhanced differentiation in automatic neurophysiological responses to infants with high and low levels of baby schema features. These findings highlight the importance of considering individual differences in continued research to further understand the complexities of sensitivity to child cues, including facial features, which will improve our understanding of the intricate neurobiological system that forms the basis of caregiving behavior.
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Metilação de DNA , Eletroencefalografia , Expressão Facial , Motivação , Ocitocina , Receptores de Ocitocina , Humanos , Feminino , Motivação/fisiologia , Ocitocina/metabolismo , Ocitocina/genética , Metilação de DNA/fisiologia , Lactente , Receptores de Ocitocina/genética , Adulto Jovem , Adulto , Comportamento Materno/fisiologia , Comportamento do Lactente/fisiologia , Masculino , Relações Mãe-FilhoRESUMO
BACKGROUND: One of the most robust risk factors for developing a mood disorder is having a parent with a mood disorder. Unfortunately, mechanisms explaining the transmission of mood disorders from one generation to the next remain largely elusive. Since timely intervention is associated with a better outcome and prognosis, early detection of intergenerational transmission of mood disorders is of paramount importance. Here, we describe the design of the Mood and Resilience in Offspring (MARIO) cohort study in which we investigate: 1. differences in clinical, biological and environmental (e.g., psychosocial factors, substance use or stressful life events) risk and resilience factors in children of parents with and without mood disorders, and 2. mechanisms of intergenerational transmission of mood disorders via clinical, biological and environmental risk and resilience factors. METHODS: MARIO is an observational, longitudinal cohort study that aims to include 450 offspring of parents with a mood disorder (uni- or bipolar mood disorders) and 100-150 offspring of parents without a mood disorder aged 10-25 years. Power analyses indicate that this sample size is sufficient to detect small to medium sized effects. Offspring are recruited via existing Dutch studies involving patients with a mood disorder and healthy controls, for which detailed clinical, environmental and biological data of the index-parent (i.e., the initially identified parent with or without a mood disorder) is available. Over a period of three years, four assessments will take place, in which extensive clinical, biological and environmental data and data on risk and resilience are collected through e.g., blood sampling, face-to-face interviews, online questionnaires, actigraphy and Experience Sampling Method assessment. For co-parents, information on demographics, mental disorder status and a DNA-sample are collected. DISCUSSION: The MARIO cohort study is a large longitudinal cohort study among offspring of parents with and without mood disorders. A unique aspect is the collection of granular data on clinical, biological and environmental risk and resilience factors in offspring, in addition to available parental data on many similar factors. We aim to investigate the mechanisms underlying intergenerational transmission of mood disorders, which will ultimately lead to better outcomes for offspring at high familial risk.
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Filho de Pais com Deficiência , Resiliência Psicológica , Criança , Humanos , Filho de Pais com Deficiência/psicologia , Estudos de Coortes , Estudos Longitudinais , Transtornos do Humor/psicologia , Pais/psicologiaRESUMO
BACKGROUND: Childhood maltreatment (CM) is a strong risk factor for psychiatric disorders but serves in its current definitions as an umbrella for various fundamentally different childhood experiences. As first step toward a more refined analysis of the impact of CM, our objective is to revisit the relation of abuse and neglect, major subtypes of CM, with symptoms across disorders. METHODS: Three longitudinal studies of major depressive disorder (MDD, N = 1240), bipolar disorder (BD, N = 1339), and schizophrenia (SCZ, N = 577), each including controls (N = 881), were analyzed. Multivariate regression models were used to examine the relation between exposure to abuse, neglect, or their combination to the odds for MDD, BD, SCZ, and symptoms across disorders. Bidirectional Mendelian randomization (MR) was used to probe causality, using genetic instruments of abuse and neglect derived from UK Biobank data (N = 143 473). RESULTS: Abuse was the stronger risk factor for SCZ (OR 3.51, 95% CI 2.17-5.67) and neglect for BD (OR 2.69, 95% CI 2.09-3.46). Combined CM was related to increased risk exceeding additive effects of abuse and neglect for MDD (RERI = 1.4) and BD (RERI = 1.1). Across disorders, abuse was associated with hallucinations (OR 2.16, 95% CI 1.55-3.01) and suicide attempts (OR 2.16, 95% CI 1.55-3.01) whereas neglect was associated with agitation (OR 1.24, 95% CI 1.02-1.51) and reduced need for sleep (OR 1.64, 95% CI 1.08-2.48). MR analyses were consistent with a bidirectional causal effect of abuse with SCZ (IVWforward = 0.13, 95% CI 0.01-0.24). CONCLUSIONS: Childhood abuse and neglect are associated with different risks to psychiatric symptoms and disorders. Unraveling the origin of these differences may advance understanding of disease etiology and ultimately facilitate development of improved personalized treatment strategies.
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BACKGROUND: The output of many healthy physiological systems displays fractal fluctuations with self-similar temporal structures. Altered fractal patterns are associated with pathological conditions. There is evidence that patients with bipolar disorder have altered daily behaviors. METHODS: To test whether fractal patterns in motor activity are altered in patients with bipolar disorder, we analyzed 2-week actigraphy data collected from 106 patients with bipolar disorder type I in a euthymic state, 73 unaffected siblings of patients, and 76 controls. To examine the link between fractal patterns and symptoms, we analyzed 180-day actigraphy and mood symptom data that were simultaneously collected from 14 patients. RESULTS: Compared to controls, patients showed excessive regularity in motor activity fluctuations at small time scales (<1.5 h) as quantified by a larger scaling exponent (α1 > 1), indicating a more rigid motor control system. α1 values of siblings were between those of patients and controls. Further examinations revealed that the group differences in α1 were only significant in females. Sex also affected the group differences in fractal patterns at larger time scales (>2 h) as quantified by scaling exponent α2. Specifically, female patients and siblings had a smaller α2 compared to female controls, indicating more random activity fluctuations; while male patients had a larger α2 compared to male controls. Interestingly, a higher weekly depression score was associated with a lower α1 in the subsequent week. CONCLUSIONS: Our results show sex- and scale-dependent alterations in fractal activity regulation in patients with bipolar disorder. The mechanisms underlying the alterations are yet to be determined.
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Transtorno Bipolar/diagnóstico , Fractais , Atividade Motora/fisiologia , Actigrafia , Adulto , Afeto , Idoso , Biomarcadores , Estudos de Casos e Controles , Ritmo Circadiano/fisiologia , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Países Baixos , Irmãos , Sono , Transtornos do Sono-Vigília/diagnósticoRESUMO
A correction to this paper has been published and can be accessed via a link at the top of the paper.
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Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. We previously developed a stress-enhanced fear learning (SEFL) paradigm in inbred mice that produces PTSD-like characteristics in a subset of mice, including persistently enhanced memory and heightened cFos in the basolateral amygdala complex (BLC) with retrieval of the remote (30-day-old) stress memory. Here, the contribution of BLC microRNAs (miRNAs) to stress-enhanced memory was investigated because of the molecular complexity they achieve through their ability to regulate multiple targets simultaneously. We performed small-RNA sequencing (smRNA-Seq) and quantitative proteomics on BLC tissue collected from mice 1 month after SEFL and identified persistently changed microRNAs, including mir-135b-5p, and proteins associated with PTSD-like heightened fear expression. Viral-mediated overexpression of mir-135b-5p in the BLC of stress-resilient animals enhanced remote fear memory expression and promoted spontaneous renewal 14 days after extinction. Conversely, inhibition of BLC mir-135b-5p in stress-susceptible animals had the opposite effect, promoting a resilient-like phenotype. mir-135b-5p is highly conserved across mammals and was detected in post mortem human amygdala, as well as human serum samples. The mir-135b passenger strand, mir-135b-3p, was significantly elevated in serum from PTSD military veterans, relative to combat-exposed control subjects. Thus, miR-135b-5p may be an important therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.
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Medo/fisiologia , Memória/fisiologia , MicroRNAs/genética , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Feminino , Humanos , Masculino , Camundongos , MicroRNAs/análise , MicroRNAs/sangueRESUMO
BACKGROUND: Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. Previous transcriptomic BD studies have had inconsistent findings due to issues such as small sample sizes and difficulty in adequately accounting for confounders like medication use. METHODS: We performed a differential expression analysis in a well-characterized BD case-control sample (Nsubjects = 480) by RNA sequencing of whole blood. We further performed co-expression network analysis, functional enrichment, and cell type decomposition, and integrated differentially expressed genes with genetic risk. RESULTS: While we observed widespread differential gene expression patterns between affected and unaffected individuals, these effects were largely linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell signaling and immune response functional annotations, among others, and were associated with neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression genetic risk based on information from genome-wide association studies, nor was gene expression associated with polygenic risk scores for BD. CONCLUSIONS: These findings suggest that BD is associated with minimal changes in whole blood gene expression independent of medication use but emphasize the importance of accounting for medication use and cell type heterogeneity in psychiatric transcriptomic studies. The results of this study add to mounting evidence of lithium's cell signaling and immune-related mechanisms.
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Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Expressão Gênica/efeitos dos fármacos , Compostos de Lítio/uso terapêutico , Adulto , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Medição de RiscoRESUMO
BACKGROUND: In a large and comprehensively assessed sample of patients with bipolar disorder type I (BDI), we investigated the prevalence of psychotic features and their relationship with life course, demographic, clinical, and cognitive characteristics. We hypothesized that groups of psychotic symptoms (Schneiderian, mood incongruent, thought disorder, delusions, and hallucinations) have distinct relations to risk factors. METHODS: In a cross-sectional study of 1342 BDI patients, comprehensive demographical and clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV (SCID-I) interview. In addition, levels of childhood maltreatment and intelligence quotient (IQ) were assessed. The relationships between these characteristics and psychotic symptoms were analyzed using multiple general linear models. RESULTS: A lifetime history of psychotic symptoms was present in 73.8% of BDI patients and included delusions in 68.9% of patients and hallucinations in 42.6%. Patients with psychotic symptoms showed a significant younger age of disease onset (ß = -0.09, t = -3.38, p = 0.001) and a higher number of hospitalizations for manic episodes (F11 338 = 56.53, p < 0.001). Total IQ was comparable between groups. Patients with hallucinations had significant higher levels of childhood maltreatment (ß = 0.09, t = 3.04, p = 0.002). CONCLUSIONS: In this large cohort of BDI patients, the vast majority of patients had experienced psychotic symptoms. Psychotic symptoms in BDI were associated with an earlier disease onset and more frequent hospitalizations particularly for manic episodes. The study emphasizes the strength of the relation between childhood maltreatment and hallucinations but did not identify distinct subgroups based on psychotic features and instead reported of a large heterogeneity of psychotic symptoms in BD.
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Transtorno Bipolar/psicologia , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/etiologia , Adulto , Experiências Adversas da Infância , Idoso , Estudos Transversais , Delusões , Feminino , Alucinações , Hospitalização/estatística & dados numéricos , Humanos , Inteligência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Transtornos Psicóticos/psicologia , Fatores de RiscoRESUMO
The notion that healthy brain function emerges from coordinated neural activity constrained by the brain's network of anatomical connections--i.e., the connectome--suggests that alterations in the connectome's wiring pattern may underlie brain disorders. Corroborating this hypothesis, studies in schizophrenia are indicative of altered connectome architecture including reduced communication efficiency, disruptions of central brain hubs, and affected "rich club" organization. Whether similar deficits are present in bipolar disorder is currently unknown. This study examines structural connectome topology in 216 bipolar I disorder patients as compared to 144 healthy controls, focusing in particular on central regions (i.e., brain hubs) and connections (i.e., rich club connections, interhemispheric connections) of the brain's network. We find that bipolar I disorder patients exhibit reduced global efficiency (-4.4%, P =0.002) and that this deficit relates (r = 0.56, P < 0.001) to reduced connectivity strength of interhemispheric connections (-13.0%, P = 0.001). Bipolar disorder patients were found not to show predominant alterations in the strength of brain hub connections in general, or of connections spanning brain hubs (i.e., "rich club" connections) in particular (all P > 0.1). These findings highlight a role for aberrant brain network architecture in bipolar I disorder with reduced global efficiency in association with disruptions in interhemispheric connectivity, while the central "rich club" system appears not to be particularly affected.
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Transtorno Bipolar/patologia , Encéfalo/patologia , Conectoma , Vias Neurais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/fisiopatologia , Mapeamento Encefálico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Adulto JovemRESUMO
BACKGROUND: Even though traumatic stress is a major risk factor for depression, most people do not develop a depression. The effects of stress may particularly emerge after repeated exposure in vulnerable individuals. Therefore, we hypothesized that (1) increased exposure to stress across the life span is associated with an increased depression risk and (2) this effect is the most pronounced in individuals with high levels of neuroticism. METHODS: We investigated the effect of childhood maltreatment, major life events, daily hassles, and a composite index thereof (cumulative stress index) on depressive symptoms and major depressive disorder (MDD) including the possible moderating role of neuroticism in a discovery sample from the general population (N = 563) and an independent replication sample from the Netherlands Study of Depression and Anxiety (N = 2,274). RESULTS: All stress domains were independently associated with depressive symptoms in the discovery sample. In the replication sample, we confirmed these findings for childhood maltreatment and daily hassles but not for major life events with depressive symptoms as outcome. Nevertheless, all stress domains significantly contributed to the presence of MDD in the replication sample. The cumulative stress index was significantly associated with depression in the discovery (ß = 1.42, P < .001) and replication sample (ß = 3.79, P < .001), especially in those individuals with high levels of trait neuroticism (discovery: ß = 0.013, P < .001; replication: ß = 0.367, P < .001). CONCLUSIONS: This is the first study to show that cumulative stress exposure across different stress domains contributes to depressive symptoms and MDD in adulthood. Moreover, we show that increased exposure to stress across the life span has more impact on vulnerable individuals with high levels of trait neuroticism.
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Transtornos de Ansiedade/epidemiologia , Maus-Tratos Infantis/estatística & dados numéricos , Depressão/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Acontecimentos que Mudam a Vida , Estresse Psicológico/epidemiologia , Adolescente , Adulto , Idoso , Maus-Tratos Infantis/psicologia , Depressão/etiologia , Transtorno Depressivo Maior/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Neuroticismo , Risco , Estresse Psicológico/complicações , Adulto JovemRESUMO
BACKGROUND: Accumulating evidence suggests that several adult mental disorders, particularly psychoses, are preceded by impairments in cognitive function, reflected in scholastic underachievement. This study investigates the association between scholastic underachievement and general mental health problems in adolescence, using delay in school progression as a marker of poor scholastic performance. METHOD: Cross-sectional secondary school survey comprising 10,803 adolescents. Participants completed the Strengths and Difficulties Questionnaire (SDQ) to assess mental health problems. The association of delayed school progression with the SDQ was investigated using logistic regression with SDQ as outcome and delayed school progression as primary exposure of interest while adjusting for socio-demographic characteristics, adverse life events, school-related factors, risk taking behaviour, healthy lifestyle and physical health. RESULTS: Unadjusted analysis showed an association between delayed school progression and total mental health problems (OR 1.83, 95% CI 1.27-2.63) in adolescents. After adjusting for other risk factors (socio-demographic factors and life events) in a logistic regression model the association between delayed school progression en mental health problems was attenuated (OR 1.33, 95% CI 0.86-2.05). CONCLUSION: Delayed school progression is associated with general mental health problems in adolescence, but this relationship is heavily confounded by other factors. A causal relationship between impaired cognitive function such as poor scholastic performance and general mental health at adolescence is less likely and delayed school progression may merely be considered an indicator of risk for mental health problems.
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Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Saúde Mental , Baixo Rendimento Escolar , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Países Baixos/epidemiologia , Fatores de Risco , Instituições Acadêmicas , Ajustamento Social , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Schizophrenia spectrum disorders and bipolar spectrum disorders are the product of both heritable and non-heritable factors, the impact of which converges at different biological levels. Recent evidence from molecular approaches has provided new insights about how environmental exposures cause persistent alterations in the regulation of gene expression, particularly by so-called epigenetic mechanisms. The aim of this review is to provide an overview of findings of epigenetic studies in psychotic disorders, summarizing findings of human and animal studies on epigenetic alterations due to postnatal environmental exposures associated with psychotic disorders. METHODS: Electronic and manual literature search of MEDLINE, EMBASE and PSYCHINFO, using a range of search terms around epigenetics, DNA methylation, histone modifications, psychoses, schizophrenia, bipolar disorder and environmental risks associated with psychotic disorders as observed in human and experimental animal studies, complemented by review articles and cross-references. RESULTS: Despite several promising findings of differential epigenetic profiles in individuals with psychotic disorders in the studies published to date, the knowledge of the role of epigenetic processes in psychotic disorder remains very limited, and should be interpreted cautiously given various challenges in this rapidly evolving field of research. CONCLUSIONS: Integration of epigenetic findings into biopsychosocial models of the etiology of psychotic disorders eventually may yield important insights into the biological underpinnings of the onset and course of psychotic disorders.
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Meio Ambiente , Epigênese Genética , Epigenômica , Transtornos Psicóticos/genética , Animais , Metilação de DNA , Humanos , Modelos GenéticosRESUMO
School environment is an important determinant of psychosocial function and may also be related to mental health. We therefore investigated whether perceived school safety, a simple measure of this environment, is related to mental health problems. In a population-based sample of 11,130 secondary school students, we analysed the relationship of perceived school safety with mental health problems using multiple logistic regression analyses to adjust for potential confounders. Mental health problems were defined using the clinical cut-off of the self-reported Strengths and Difficulties Questionnaire. School safety showed an exposure-response relationship with mental health problems after adjustment for confounders. Odds ratios increased from 2.48 ("sometimes unsafe") to 8.05 ("very often unsafe"). The association was strongest in girls and young and middle-aged adolescents. Irrespective of the causal background of this association, school safety deserves attention either as a risk factor or as an indicator of mental health problems.
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Transtornos Mentais/psicologia , Segurança , Instituições Acadêmicas , Percepção Social , Estudantes/psicologia , Adolescente , Bullying/psicologia , Criança , Vítimas de Crime/psicologia , Vítimas de Crime/estatística & dados numéricos , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Países Baixos , Fatores de Risco , Ajustamento Social , Meio Social , Inquéritos e Questionários , Adulto JovemRESUMO
Genomic copy number variations (CNVs) and increased parental age are both associated with the risk to develop a variety of clinical neuropsychiatric disorders such as autism, schizophrenia and bipolar disorder. At the same time, it has been shown that the rate of transmitted de novo single nucleotide mutations is increased with paternal age. To address whether paternal age also affects the burden of structural genomic deletions and duplications, we examined various types of CNV burden in a large population sample from the Netherlands. Healthy participants with parental age information (n = 6,773) were collected at different University Medical Centers. CNVs were called with the PennCNV algorithm using Illumina genome-wide SNP array data. We observed no evidence in support of a paternal age effect on CNV load in the offspring. Our results were negative for global measures as well as several proxies for de novo CNV events in this unique sample. While recent studies suggest de novo single nucleotide mutation rate to be dominated by the age of the father at conception, our results strongly suggest that at the level of global CNV burden there is no influence of increased paternal age. While it remains possible that local genomic effects may exist for specific phenotypes, this study indicates that global CNV burden and increased father's age may be independent disease risk factors.
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Algoritmos , Variações do Número de Cópias de DNA , Taxa de Mutação , Mutação , Pais , Polimorfismo de Nucleotídeo Único , Adulto , Fatores Etários , Idoso , Feminino , Genética Populacional , Humanos , Masculino , Pessoa de Meia-Idade , Países BaixosRESUMO
OBJECTIVES: We sought to determine whether the risk of relapse in patients with bipolar disorder is higher after discontinuation and restart of lithium treatment as compared to continuous lithium treatment in these same patients. METHODS: We conducted literature searches in the Pubmed, Embase, Cochrane, and PsycINFO databases with cross-reference checks. Relevant data were extracted and pooled for meta-analysis. RESULTS: Five relevant studies were included for review, of which three studies qualified for the meta-analysis and included a total of 212 analyzed cases. Two studies found lithium to be less effective after discontinuation and reintroduction and three studies found no decreased effectiveness. The pooled odds ratio for the occurrence of one or more relapses after interruption of lithium treatment compared to continuous treatment was 1.40 (95% confidence interval: 0.85-2.31; p = 0.19). CONCLUSIONS: Although studies are scarce, review and meta-analysis of the available literature does not provide convincing evidence that lithium is less effective when treatment is discontinued and restarted, compared to uninterrupted treatment.
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Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Cloreto de Lítio/uso terapêutico , Resultado do Tratamento , Esquema de Medicação , Humanos , RecidivaRESUMO
PURPOSE: Both increased as well as decreased cancer mortality among psychiatric patients has been reported, but competing death causes were not included in the analyses. This study aims to investigate whether observed cancer mortality in patients with psychiatric disorders might be biased by competing death causes. METHOD: In this retrospective cohort study on data from the Psychiatric Case Register Middle Netherlands linked to the death register of Statistics Netherlands, the risk of cancer death among patients with schizophrenia (N = 4,590), bipolar disorder (N = 2,077), depression (N = 15,130) and their matched controls (N = 87,405) was analyzed using a competing risk model. RESULTS: Compared to controls, higher hazards of cancer death were found in patients with schizophrenia (HR = 1.61, 95 % CI 1.26-2.06), bipolar disorder (HR = 1.20, 95 % CI 0.81-1.79) and depression (HR = 1.26, 95 % CI 1.10-1.44). However, the HRs of death due to suicide and other death causes were more elevated. Consequently, among those who died, the 12-year cumulative risk of cancer death was significantly lower. CONCLUSIONS: Our analysis shows that, compared to the general population, psychiatric patients are at higher risk of dying from cancer, provided that they survive the much more elevated risks of suicide and other death causes.
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Transtorno Bipolar/epidemiologia , Transtorno Depressivo/epidemiologia , Neoplasias/mortalidade , Esquizofrenia/epidemiologia , Adulto , Transtorno Bipolar/complicações , Transtorno Bipolar/diagnóstico , Estudos de Casos e Controles , Transtorno Depressivo/complicações , Transtorno Depressivo/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Razão de Chances , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Esquizofrenia/complicações , Esquizofrenia/diagnóstico , Fatores Socioeconômicos , Fatores de TempoRESUMO
BACKGROUND: Electroconvulsive therapy (ECT) in patients with major depression is associated with volume changes and markers of neuroplasticity in the hippocampus, in particular in the dentate gyrus. It is unclear if these changes are associated with cognitive side effects. OBJECTIVES: We investigated whether changes in cognitive functioning after ECT were associated with hippocampal structural changes. It was hypothesized that 1) volume increase of hippocampal subfields and 2) changes in perfusion and diffusion of the hippocampus correlated with cognitive decline. METHODS: Using ultra high field (7 T) MRI, intravoxel incoherent motion and volumetric data were acquired and neurocognitive functioning was assessed before and after ECT in 23 patients with major depression. Repeated measures correlation analysis was used to examine the relation between cognitive functioning and structural characteristics of the hippocampus. RESULTS: Left hippocampal volume, left and right dentate gyrus and right CA1 volume increase correlated with decreases in verbal memory functioning. In addition, a decrease of mean diffusivity in the left hippocampus correlated with a decrease in letter fluency. LIMITATIONS: Due to methodological restrictions direct study of neuroplasticity is not possible. MRI is used as an indirect measure. CONCLUSION: As both volume increase in the hippocampus and MD decrease can be interpreted as indirect markers for neuroplasticity that co-occur with a decrease in cognitive functioning, our results may indicate that neuroplastic processes are affecting cognitive processes after ECT.
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Disfunção Cognitiva , Transtorno Depressivo Maior , Eletroconvulsoterapia , Humanos , Eletroconvulsoterapia/efeitos adversos , Eletroconvulsoterapia/métodos , Projetos Piloto , Resultado do Tratamento , Hipocampo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/terapia , Imageamento por Ressonância Magnética , PerfusãoRESUMO
BACKGROUND: The predominant model for regulation of gene expression through DNA methylation is an inverse association in which increased methylation results in decreased gene expression levels. However, recent studies suggest that the relationship between genetic variation, DNA methylation and expression is more complex. RESULTS: Systems genetic approaches for examining relationships between gene expression and methylation array data were used to find both negative and positive associations between these levels. A weighted correlation network analysis revealed that i) both transcriptome and methylome are organized in modules, ii) co-expression modules are generally not preserved in the methylation data and vice-versa, and iii) highly significant correlations exist between co-expression and co-methylation modules, suggesting the existence of factors that affect expression and methylation of different modules (i.e., trans effects at the level of modules). We observed that methylation probes associated with expression in cis were more likely to be located outside CpG islands, whereas specificity for CpG island shores was present when methylation, associated with expression, was under local genetic control. A structural equation model based analysis found strong support in particular for a traditional causal model in which gene expression is regulated by genetic variation via DNA methylation instead of gene expression affecting DNA methylation levels. CONCLUSIONS: Our results provide new insights into the complex mechanisms between genetic markers, epigenetic mechanisms and gene expression. We find strong support for the classical model of genetic variants regulating methylation, which in turn regulates gene expression. Moreover we show that, although the methylation and expression modules differ, they are highly correlated.
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Células Sanguíneas/metabolismo , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Variação Genética , Transcriptoma/genética , Células Sanguíneas/química , Ilhas de CpG/genética , Genótipo , Humanos , Modelos Lineares , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
PURPOSE: To investigate familial clustering of schizophrenia, bipolar disorder, and major depressive disorder. METHODS: Combining data from a psychiatric case registry and Statistics Netherlands provided information on 4,673 affected probands and 18,692 matched population controls. RESULTS: Probands with schizophrenia had relative risks (RRs) for having a sibling with schizophrenia of 3.77 (95% confidence interval (CI): 2.60-5.46) and with bipolar disorder of 1.79 (95% CI: 0.64-4.96) as compared with a reference proband. Probands affected with bipolar disorder have an RR of 6.51 (95% CI: 2.60-16.29) for having a sibling with bipolar disorder and of 1.71 (95% CI: 0.71-4.14) for having a sibling with schizophrenia as compared with a reference proband. Probands affected with major depressive disorder also have increased risk for having a sibling with schizophrenia (RR: 2.04, 95% CI: 1.54-2.72) as compared with a reference proband, which was similar to the risk for having a sibling with major depressive disorder (RR: 1.91, 95% CI: 1.63-2.24) or bipolar disorder (RR: 2.06, 95% CI: 1.18-3.60). CONCLUSION: Our findings suggest, as previous studies have, that risk across schizophrenia and bipolar disorder is considerably lower (twofold) than within diagnostic entities, whereas for major depressive disorder risk is similar within and across diagnostic entities.
Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Esquizofrenia/epidemiologia , Adulto , Fatores Etários , Análise por Conglomerados , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Risco , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: Schizophrenia is a complex psychiatric disorder characterized by high phenotypic heterogeneity. Previous studies have distinguished between familial and sporadic forms of schizophrenia and have suggested clinical differentiation between patients and relatives from sporadic and multiplex families. We will introduce a more refined method to distinguish between family subtypes based on psychosis dimension profiles in the relatives of schizophrenia patients. METHODS: Positive, negative, disorganization, mania, and depression scores were assessed in 1,392 relatives. Mixed Model Latent Class Analysis was used to identify family subtypes. A family subtype is a relatively homogeneous group of families with similar symptom profiles in the relatives in these families. Next, we investigated in 616 schizophrenia patients whether family subtype was associated with symptom profiles, IQ, cannabis dependence/abuse, or age of onset of psychosis. RESULTS: Based on the data of relatives, we identified two different family types: "healthy" and "at risk for psychiatric disorder". Patients from at risk families obtained higher positive scores compared to patients from healthy families (Wald(1) =6.6293, p=0.010). No significant differences were found in any of the remaining variables. CONCLUSIONS: Our findings confirm the existence of high-risk families and although we did not establish an etiological basis for the distinction between family types, genetic studies might reveal whether family subtype is associated with genetic heterogeneity.