RESUMO
The endocannabinoid system is an important regulator of emotional responses such as fear, and a number of studies have implicated endocannabinoid signaling in anxiety. The fatty acid amide hydrolase (FAAH) C385A polymorphism, which is associated with enhanced endocannabinoid signaling in the brain, has been identified across species as a potential protective factor from anxiety. In particular, adults with the variant FAAH 385A allele have greater fronto-amygdala connectivity and lower anxiety symptoms. Whether broader network-level differences in connectivity exist, and when during development this neural phenotype emerges, remains unknown and represents an important next step in understanding how the FAAH C385A polymorphism impacts neurodevelopment and risk for anxiety disorders. Here, we leveraged data from 3,109 participants in the nationwide Adolescent Brain Cognitive Development Studyâ (10.04 ± 0.62 years old; 44.23% female, 55.77% male) and a cross-validated, data-driven approach to examine associations between genetic variation and large-scale resting-state brain networks. Our findings revealed a distributed brain network, comprising functional connections that were both significantly greater (95% CI for p values = [<0.001, <0.001]) and lesser (95% CI for p values = [0.006, <0.001]) in A-allele carriers relative to non-carriers. Furthermore, there was a significant interaction between genotype and the summarized connectivity of functional connections that were greater in A-allele carriers, such that non-carriers with connectivity more similar to A-allele carriers (i.e., greater connectivity) had lower anxiety symptoms (ß = -0.041, p = 0.030). These findings provide novel evidence of network-level changes in neural connectivity associated with genetic variation in endocannabinoid signaling and suggest that genotype-associated neural differences may emerge at a younger age than genotype-associated differences in anxiety.
Assuntos
Tonsila do Cerebelo , Endocanabinoides , Adolescente , Tonsila do Cerebelo/fisiologia , Ansiedade/genética , Transtornos de Ansiedade , Endocanabinoides/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3- to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by â¼12 y of age and are paralleled by changes in anxiety-related behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.
Assuntos
Endocanabinoides/metabolismo , Lobo Frontal/metabolismo , Lobo Límbico/metabolismo , Rede Nervosa/metabolismo , Transdução de Sinais/fisiologia , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Feminino , Lobo Frontal/citologia , Humanos , Lobo Límbico/citologia , Masculino , Camundongos , Camundongos Transgênicos , Rede Nervosa/citologia , Especificidade da EspécieRESUMO
The serotonin transporter (SERT) is a major regulator of serotonergic neurotransmission and anxiety-related behaviors. SERT is expressed in two alternative polyadenylation forms that differ by an evolutionarily conserved element in the 3' untranslated region of its mRNA. Expression of SERT mRNA containing the distal polyadenylation element is associated with decreased anxiety-related behaviors in mice and humans, suggesting that this element has behaviorally relevant modulatory effects on SERT expression. We have identified heterogeneous nuclear ribonucleoprotein K (hnRNPK), a protein known to integrate multiple signal transduction pathways with gene expression, as a SERT distal polyadenylation element binding protein. This interaction is functionally meaningful because genetic manipulation of hnRNPK alters expression of the SERT protein. Furthermore, the trophic factor S100ß induces Src-family kinase-mediated tyrosine phosphorylation of hnRNPK and increased SERT expression. These results identify a previously unknown mechanism of regulated SERT expression and provide a putative mechanism by which the SERT distal polyadenylation element modulates anxiety-related behaviors.
Assuntos
Ansiedade/metabolismo , Poli A/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Ribonucleoproteínas/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Animais , Ansiedade/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K , Humanos , Camundongos , MicroRNAs/metabolismo , Fatores de Crescimento Neural/metabolismo , Fosforilação , Ligação Proteica , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/metabolismo , Quinases da Família src/metabolismoRESUMO
There are no known genetic variants with large effects on susceptibility to major depressive disorder (MDD). Although one proposed study approach is to increase sensitivity by increasing sample sizes, another is to focus on families with multiple affected individuals to identify genes with rare or novel variants with strong effects. Choosing the family-based approach, we performed whole-exome analysis on affected individuals (n = 12) across five MDD families, each with at least five affected individuals, early onset, and prepubertal diagnoses. We identified 67 genes where novel deleterious variants were shared among affected relatives. Gene ontology analysis shows that of these 67 genes, 18 encode transcriptional regulators, eight of which are expressed in the human brain, including four KRAB-A box-containing Zn(2+) finger repressors. One of these, ZNF34, has been reported as being associated with bipolar disorder and as differentially expressed in bipolar disorder patients compared to healthy controls. We found a novel variant-encoding a non-conservative P17R substitution in the conserved repressor domain of ZNF34 protein-segregating completely with MDD in all available individuals in the family in which it was discovered. Further analysis showed a common ZNF34 coding indel segregating with MDD in a separate family, possibly indicating the presence of an unobserved, linked, rare variant in that particular family. Our results indicate that genes encoding transcription factors expressed in the brain might be an important group of MDD candidate genes and that rare variants in ZNF34 might contribute to susceptibility to MDD and perhaps other affective disorders.
Assuntos
Proteínas de Ligação a DNA/genética , Transtorno Depressivo Maior/genética , Família , Polimorfismo de Nucleotídeo Único/genética , Fatores Genéricos de Transcrição/genética , Fatores de Transcrição/genética , Idade de Início , Alelos , Exoma/genética , Feminino , Humanos , Masculino , Mutação/genética , Linhagem , Análise de Sequência de DNARESUMO
Family studies have shown that MDD is highly transmittable but have not studied its heritability. Twin studies show heritability of about 40% and do not include anxiety disorders. We assessed heritability of MDD and comorbid anxiety disorders in a multigenerational study of family members at high risk for MDD. In addition, we tested the hypothesis that examined clinical subtypes of MDD defined by early and late age of onset would be under relatively stronger genetic control than broadly defined DSM-IV MDD. The first generation with moderate to severe MDD was recruited from an ambulatory psychiatric treatment setting, and their descendants in the second, third, and fourth generation, were interviewed by clinicians up to six times during a 30-year period. Lifetime rates of MDD and anxiety disorders were collected for 545 participants from 65 multigenerational families. The heritability (h2 ) of MDD in this high risk sample was estimated at 67%. Anxiety and sequential comorbidity of anxiety disorders and MDD revealed h2 of 49% and 53%, respectively, and strong positive genetic correlation (rhog = 0.92, P = 7.3 × 10-7 ). Early onset MDD did not appear to be under greater genetic control than broadly defined DSM-IV MDD. Individuals who are direct descendants of subjects ascertained for moderate to severe MDD have strong genetic vulnerability to develop anxiety or MDD. Our findings support family based studies as appropriate and useful design to understand the heritability of common disorders such as MDD. © 2016 Wiley Periodicals, Inc.
Assuntos
Transtornos de Ansiedade/genética , Transtorno Depressivo Maior/genética , Adolescente , Adulto , Idade de Início , Idoso , Ansiedade/genética , Criança , Comorbidade , Depressão/genética , Manual Diagnóstico e Estatístico de Transtornos Mentais , Família/psicologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Escalas de Graduação Psiquiátrica , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
A fundamental issue in psychiatric medicine is the lack of empirical evidence indicating when, during development, a treatment will be most effective for a patient. We review behavioral and brain changes that occur across development, focusing on the period of adolescence, when there is a peak in diagnosis of many psychiatric disorders. We use anxiety disorders as an example because of their high prevalence in youth (affecting as many as 1 in 10). Basic forms of fear learning, which are at the core of anxiety disorders and are the targets of behavioral therapeutics, are examined as a function of age. We also discuss how fear learning has been genetically modulated in mice and humans. Based on these findings, we provide future directions for determining the efficacy of innovative therapies and preventive strategies for anxiety disorders as a function of age and potential genetic effects inferred from mice and humans.
Assuntos
Terapia Comportamental/métodos , Encéfalo/crescimento & desenvolvimento , Diagnóstico por Imagem/métodos , Transtornos Mentais , Animais , Modelos Animais de Doenças , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/genética , Transtornos Mentais/terapia , Camundongos , Escalas de Graduação PsiquiátricaRESUMO
Growing evidence suggests serotonin's role in anxiety and depression is mediated by its effects on learned fear associations. Pharmacological and genetic manipulations of serotonin signaling in mice alter the retention of fear extinction learning, which is inversely associated with anxious temperament in mice and humans. Here, we test whether genetic variation in serotonin signaling in the form of a common human serotonin transporter polyadenylation polymorphism (STPP/rs3813034) is associated with spontaneous fear recovery after extinction. We show that the risk allele of this polymorphism is associated with impaired retention of fear extinction memory and heightened anxiety and depressive symptoms. These STPP associations in humans mirror the phenotypic effects of serotonin transporter knockout in mice, highlighting the STPP as a potential genetic locus underlying interindividual differences in serotonin transporter function in humans. Furthermore, we show that the serotonin transporter polyadenylation profile associated with the STPP risk allele is altered through the chronic administration of fluoxetine, a treatment that also facilitates retention of extinction learning. The propensity to form persistent fear associations due to poor extinction recall may be an intermediate phenotype mediating the effects of genetic variation in serotonergic function on anxiety and depression. The consistency and specificity of these data across species provide robust support for this hypothesis and suggest that the little-studied STPP may be an important risk factor for mood and anxiety disorders in humans.
Assuntos
Medo , Memória , Poli A/metabolismo , Polimorfismo Genético , Receptores de Serotonina/metabolismo , Alelos , Animais , Ansiedade/genética , Depressão/genética , Fluoxetina/farmacologia , Variação Genética , Humanos , Camundongos , Receptores de Serotonina/genéticaRESUMO
The only evidence-based behavioral treatment for anxiety and stress-related disorders involves desensitization techniques that rely on principles of extinction learning. However, 40% of patients do not respond to this treatment. Efforts have focused on individual differences in treatment response, but have not examined when, during development, such treatments may be most effective. We examined fear-extinction learning across development in mice and humans. Parallel behavioral studies revealed attenuated extinction learning during adolescence. Probing neural circuitry in mice revealed altered synaptic plasticity of prefrontal cortical regions implicated in suppression of fear responses across development. The results suggest a lack of synaptic plasticity in the prefrontal regions, during adolescence, is associated with blunted regulation of fear extinction. These findings provide insight into optimizing treatment outcomes for when, during development, exposure therapies may be most effective.
Assuntos
Transtornos de Ansiedade/psicologia , Transtornos de Ansiedade/terapia , Condicionamento Psicológico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Plasticidade Neuronal/fisiologia , Adolescente , Adulto , Análise de Variância , Animais , Criança , Feminino , Resposta Galvânica da Pele , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Microscopia de Interferência , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Adolescence represents a uniquely sensitive developmental stage in the transition from childhood to adulthood. During this transition, neuronal circuits are particularly susceptible to modification by experience. In addition, adolescence is a stage in which the incidence of anxiety disorders peaks in humans and over 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents. While postnatal critical periods of plasticity for primary sensory processes, such as in the visual system are well established, less is known about potential critical or sensitive periods for fear learning and memory. Here, we review the non-linear developmental aspects of fear learning and memory during a transition period into and out of adolescence. We also review the literature on the non-linear development of GABAergic neurotransmission, a key regulator of critical period plasticity. We provide a model that may inform improved treatment strategies for children and adolescents with fear-related disorders.
Assuntos
Período Crítico Psicológico , Medo/fisiologia , Aprendizagem/fisiologia , Memória/fisiologia , Adolescente , Animais , Transtornos de Ansiedade/etiologia , Criança , Condicionamento Psicológico/fisiologia , Extinção Psicológica/fisiologia , Humanos , Camundongos , Plasticidade Neuronal/fisiologia , Ratos , Receptores de GABA/fisiologiaRESUMO
OBJECTIVE: A large literature has identified exposure to early caregiving adversities as a potent risk for developing affective psychopathology, with depression, in particular, increasing across childhood into adolescence. Evidence suggests telomere erosion, a marker of biological aging, may underlie associations between adverse early-life experiences and later depressive behavior; yet, little is understood about this association during development. METHOD: The current accelerated longitudinal study examined concurrent telomere length and depressive symptoms concurrently, 2 and 4 years later, from the preschool period through adolescence among children exposed (n =116) and not exposed (n = 242) to early previous institutional (PI) care. RESULTS: PI care was associated with shorter telomeres on average and with quadratic age-related growth in depressive symptoms, indicating a steeper association between PI care and depressive symptoms in younger age groups that leveled off in adolescence. Contrary to studies in adult samples, telomere length was not associated with depressive symptoms, and it did not predict future symptoms. CONCLUSION: These findings indicate that early caregiving disruptions increase the risk for both accelerated biological aging and depressive symptoms, although these variables did not correlate with each other during this age range.
Assuntos
Depressão , Encurtamento do Telômero , Adulto , Criança , Pré-Escolar , Adolescente , Humanos , Depressão/genética , Depressão/diagnóstico , Estudos Longitudinais , Psicopatologia , TelômeroRESUMO
Adverse early care is associated with attention regulatory problems, but not all so exposed develop attention problems. In a sample of 612 youth (girls = 432, M = 11.82 years, SD = 1.5) adopted from institutions (e.g., orphanages) in 25 countries, we examined whether the Val66Met polymorphism of the brain-derived neurotrophic factor gene moderates attention problems associated with the duration of institutional care. Parent-reported attention problem symptoms were collected using the MacArthur Health and Behavior Questionnaire. DNA was genotyped for the brain-derived neurotrophic factor Val66Met (rs6265) single nucleotide polymorphism. Among youth from Southeast (SE) Asia, the predominant genotype was valine/methionine (Val/Met), whereas among youth from Russia/Europe and Caribbean/South America, the predominant genotype was Val/Val. For analysis, youth were grouped as carrying Val/Val or Met/Met alleles. Being female, being from SE Asia, and being younger when adopted were associated with fewer attention regulatory problem symptoms. Youth carrying at least one copy of the Met allele were more sensitive to the duration of deprivation, yielding an interaction that followed a differential susceptibility pattern. Thus, youth with Val/Met or Met/Met genotypes exhibited fewer symptoms than Val/Val genotypes when adoption was very early and more symptoms when adoption occurred later in development. Similar patterns were observed when SE Asian youth and youth from other parts of the world were analyzed separately.
Assuntos
Adoção/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Atenção , Fator Neurotrófico Derivado do Encéfalo/genética , Carência Psicossocial , Adolescente , Fatores Etários , Criança , Feminino , Predisposição Genética para Doença , Humanos , Modelos Lineares , Masculino , Orfanatos , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Fatores de TempoRESUMO
Charney discusses the growing realization in the postgenomic era that genomic biology deviates from Mendelian assumptions at the heart of genetic heritability and association studies. Given the complexity of genomic biology, how are we to identify meaningful genetic factors that contribute to behavioral? One response is to make genetic variants the focus of biological rather than statistical analyses of behavior.
Assuntos
Genética Comportamental , Genômica , Feminino , Humanos , GravidezRESUMO
Posttraumatic stress disorder (PTSD) is a significant public health issue. Yet, there are limited treatment options and no data to suggest which treatment will work for whom. We tested the efficacy of virtual reality exposure (VRE) or prolonged imaginal exposure (PE), augmented with D-cycloserine (DCS) for combat-related PTSD. As an exploratory aim, we examined whether brain-derived neurotrophic factor (BDNF) and fatty acid amide hydrolase (FAAH) moderated treatment response. Military personnel with PTSD (n = 192) were recruited into a multisite double-blind randomized controlled trial to receive nine weeks of VRE or PE, with DCS or placebo. Primary outcome was the improvement in symptom severity. Randomization was stratified by comorbid depression (MDD) and site. Participants in both VRE and PE showed similar meaningful clinical improvement with no difference between the treatment groups. A significant interaction (p = 0.45) suggested VRE was more effective for depressed participants (CAPS difference M = 3.51 [95% CI 1.17-5.86], p = 0.004, ES = 0.14) while PE was more effective for nondepressed participants (M = -8.87 [95% CI -11.33 to -6.40], p < 0.001, ES = -0.44). The main effect of DCS vs. placebo was not significant. Augmentation by MDD interaction (p = 0.073) suggested that depressed participants improved more on placebo (M = -8.43 [95% CI -10.98 to -5.88], p < 0.001, ES = -0.42); DCS and placebo were equally effective for nondepressed participants. There was an apparent moderating effect of BDNF Val66Met polymorphism on DCS augmentation (ES = 0.67). Met66 allele carriers improved more on DCS (ES = -0.25). FAAH 385 A carriers improved more than non-carriers (ES = 0.33), particularly those with MDD (ES = 0.62). This study provides a step toward precision therapeutics for PTSD by demonstrating that comorbid MDD and genetic markers may help guide treatment selection.ClinicalTrials.gov Identifier: NCT01352637.
Assuntos
Terapia Implosiva , Nootrópicos , Transtornos de Estresse Pós-Traumáticos , Realidade Virtual , Fator Neurotrófico Derivado do Encéfalo/genética , Ciclosserina/uso terapêutico , Humanos , Nootrópicos/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/terapia , Resultado do TratamentoRESUMO
SLC18A2 encodes the vesicular monoamine transporter 2 protein that regulates neurotransmission and reduces cytosolic toxicity of monoamines. Deletion of this gene causes lethality in mice, and DNA sequence variation in this gene is associated with alcoholism and Parkinson's disease, among other disorders. The Caucasian SLC18A2 promoter has at least 20 haplotypes (A-T), with A representing two-thirds of 1460 chromosomes. It is not known why A is selected in the human lineage. To understand the selection, here we took a functional approach by investigating the regulations of 4 representative haplotypes (A, C, G, and T) by 17 agents. We show that 76.5% of the agents were able to regulate A but only 11.8-23.5% of them regulated the 3 other infrequent ones, observing a positive correlation between haplotype frequency and regulatability. Pathway and molecular analyses revealed five signaling hubs that regulate the four haplotypes differentially, probably through targeting the polymorphic core promoter region. These findings suggest that greater diversity of transcriptional regulations is the driving force for the haplotype selection in SLC18A2.
Assuntos
Regulação da Expressão Gênica , Seleção Genética , Proteínas Vesiculares de Transporte de Monoamina/genética , Linhagem Celular , Variação Genética , Haplótipos , Humanos , Regiões Promotoras Genéticas , Transcrição GênicaRESUMO
OBJECTIVES: structural abnormalities in the hippocampus have been implicated in the pathophysiology of major depressive disorder (MDD). The brain-derived neurotrophic factor (BDNF) val66met polymorphism may contribute to these abnormalities and therefore confer vulnerability to MDD. This study examined whether there is a relationship among BDNF genotype, hippocampal volumes, and MDD in older adults. METHODS: thirty-three older adults with MDD and 23 psychiatrically normal comparison subjects were studied. Structural magnetic resonance imaging analysis was used to quantify hippocampal volumes. A repeated-measures analysis of covariance examined the relationships among BDNF val66met (val/val, met carrier), diagnosis (depressed, nondepressed), and hippocampal volumes (right, left). Age, gender, education, and whole brain volume were included as covariates. RESULTS: elderly MDD BDNF val/val homozygotes had significantly higher right hippocampal volumes compared with nondepressed val/val subjects. However, there was no difference between the depressed and healthy nondepressed met carriers. In addition, depressed met carriers had an earlier age of onset of depressive illness than val/val homozygotes, but age of onset did not moderate the relationship between hippocampal volumes and MDD diagnosis. CONCLUSION: these results provide preliminary evidence of a neuroprotective role of the val/val genotype, suggesting that neurotrophic factor production protects against pathophysiological processes triggered by depression in older adults with later age of onset of MDD. The BDNF val66met polymorphism may play a salient role in structural alterations of the hippocampus in older adults with MDD.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Hipocampo/patologia , Idoso , Alelos , Atrofia/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Adolescence reflects a period of increased rates of anxiety, depression, and suicide. Yet most teens emerge from this period with a healthy, positive outcome. In this article, we identify biological factors that may increase risk for some individuals during this developmental period by: (1) examining changes in neural circuitry underlying core phenotypic features of anxiety as healthy individuals transition into and out of adolescence; (2) examining genetic factors that may enhance the risk for psychopathology in one individual over another using translation from mouse models to human neuroimaging and behavior; and (3) examining the effects of early experiences on core phenotypic features of anxiety using human neuroimaging and behavioral approaches. Each of these approaches alone provides only limited information on genetic and environmental influences on complex human behavior across development. Together, they reflect an emerging field of translational developmental neuroscience in forming important bridges between animal models of neurodevelopmental and neuropsychiatric disorders.
Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/fisiopatologia , Modelos Animais de Doenças , Rede Nervosa/fisiopatologia , Fenótipo , Adolescente , Adulto , Tonsila do Cerebelo/fisiopatologia , Animais , Transtornos de Ansiedade/psicologia , Mapeamento Encefálico , Criança , Extinção Psicológica/fisiologia , Expressão Facial , Medo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Camundongos , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Percepção Visual/fisiologiaRESUMO
Excitement with the publication of the human genome has served as catalyst for scientists to uncover the functions of specific genes. The main avenues for understanding gene function have been in behavioral genetics on one end and on the other end, molecular mouse models. Attempts to bridge these approaches have used brain imaging to conveniently link anatomical abnormalities seen in knockout/transgenic mouse models and abnormal patterns of brain activity seen in humans. Although a convenient approach, this article provides examples of challenges for imaging genetics, its application to developmental questions, and promises for future directions. Attempts to link genes, brain, and behavior using behavioral genetics, imaging genetics, and mouse models of behavior are described. Each of these approaches alone, provide limited information on gene function in complex human behavior, but together, they are forming bridges between animal models and human psychiatric disorders.
Assuntos
Comportamento/fisiologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Diagnóstico por Imagem/métodos , Genética Comportamental/métodos , Animais , Humanos , Modelos NeurológicosRESUMO
BACKGROUND: PTSD, which has been identified in up to 23% of post-9-11 veterans, often results in a chronic, pernicious course. Thus, effective treatments are imperative. The Institute of Medicine (IOM) concluded that the only intervention for PTSD with sufficient evidence to conclude efficacy is exposure therapy. This Phase III trial compares the efficacy of exposure therapy for combat-related PTSD delivered in two different formats- via virtual reality exposure therapy (VRE) or prolonged exposure therapy (PE)- combined with D-Cycloserine (DCS), a cognitive enhancer shown to facilitate the extinction of fear. METHODS/DESIGN: Military personnel of any duty status and civilians deployed to Iraq and Afghanistan were eligible. Participants were randomly assigned to 9 sessions of exposure therapy (VRE or PE) and medication (50â¯mg DCS or placebo). Participants were treated at three geographically diverse sites. Participants were re-assessed at 3-months post-treatment. The co-primary hypotheses are that (1) DCS will augment response to exposure therapy (both VRE and PE) on PTSD symptoms; (2) VRE will be associated with greater improvement than PE. Genetic and psychophysiological markers will be evaluated as potential moderators and mediators of treatment outcomes as well as secondary outcomes. DISCUSSION: This study is the first to compare the relative efficacy of DCS-augmented VRE versus PE on PTSD symptoms. The design has several advantages: participants received an active, effective treatment and predictors of response to treatment included genetic and psychobiological measures. The results may directly influence the future delivery of services, and contribute to the development of a standardized treatment protocol. TRIAL REGISTRATION: NCT01352637.
Assuntos
Ciclosserina/uso terapêutico , Terapia Implosiva/métodos , Transtornos de Estresse Pós-Traumáticos/terapia , Veteranos/psicologia , Terapia de Exposição à Realidade Virtual/métodos , Terapia Combinada , Ciclosserina/administração & dosagem , Humanos , Transtornos de Estresse Pós-Traumáticos/genéticaRESUMO
Association studies have been proposed to identify the genetic determinants of complex neuropsychiatric traits. Although such studies of candidate genes offer great potential to identify genetic variants that contribute to the expression of psychiatric disease, no consistent associations have been identified. Studies to date have focused on candidate genes that are selected for analysis on the basis of incomplete information about gene function in the brain, therefore the majority of genes expressed in the brain have been ignored. Additionally, most genetic determinants of psychiatric disease will probably be of modest effect and therefore require association studies of large samples. As genomic technologies advance, massive genotyping of large samples should allow identification of alleles that contribute to psychopathology.
Assuntos
Predisposição Genética para Doença , Genoma Humano , Transtornos Mentais/genética , Interpretação Estatística de Dados , HumanosRESUMO
GSTs are a family of inducible phase II enzymes that may play a neuroprotective role in Parkinson's disease (PD). GSTs may also modify PD risk by metabolizing compounds in cigarettes, as cigarette smoking is generally found to be associated with a decrease in PD risk. Using a population-based case-control study design, we examined polymorphisms of the mu, omega, pi, and theta classes of GST to elucidate the main effects and smoking-GST interactions on PD risk. From three rural California counties, we recruited 289 incident idiopathic PD cases, clinically confirmed by our study neurologist, and 270 population controls, marginally matched by age, gender, and race. We assessed main gene polymorphism associations and evaluated interactions between smoking and GST polymorphisms as departures from a multiplicative scale adjusting for age, gender, and race. We also restricted analyses to Caucasian subjects to address the potential for population stratification (n=235 cases, 220 controls). Among Caucasians, we observed a risk reduction in subjects carrying at least one variant allele for GSTO1 (OR=0.68, 95% CI: 0.47-0.98) and also GSTO2 (OR=0.64, 95% CI: 0.44-0.93); both genes were in strong linkage disequilibrium. No main gene effects were observed for the remaining polymorphisms. We noted a multiplicative interaction between ever having smoked regularly and GSTO1 (OR(interaction)=0.55, 95% CI: 0.33-0.92) and GSTO2 (OR(interaction)=0.54, 95% CI: 0.32-0.90). Results were similar when combining all races. These findings and the paucity of similar studies suggest a need for further inquiry into the association between GSTs, smoking, and PD risk.