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1.
Artigo em Inglês | MEDLINE | ID: mdl-31444036

RESUMO

The gene coding for glycine receptor ß subunits (GLRB) has been found to be related to panic disorder and agoraphobia (PD/AG) and to be associated with altered insular BOLD activation during fear conditioning, as an intermediate phenotype of defensive system reactivity in healthy subjects. In a multicenter clinical trial on PD/AG patients we investigated in three sub-samples whether GLRB allelic variation (A/G; A-allele identified as «risk¼) in the single nucleotide polymorphism rs7688285 was associated with autonomic (behavioral avoidance test BAT; n = 267 patients) and neural (differential fear conditioning; n = 49 patients, n = 38 controls) measures, and furthermore with responding towards exposure-based cognitive behavioral therapy (CBT, n = 184 patients). An interaction of genotype with current PD/AG diagnosis (PD/AG vs. controls; fMRI data only) and their modification after CBT was tested as well. Exploratory fMRI results prior to CBT, revealed A-allele carriers irrespective of diagnostic status to show overall higher BOLD activation in the hippocampus, motor cortex (MC) and insula. Differential activation in the MC, anterior cingulate cortex (ACC) and insula was found in the interaction genotype X diagnosis. Differential activation in ACC and hippocampus was present in differential fear learning. ACC activation was modified after treatment, while no overall rs7688285 dependent effect on clinical outcomes was found. On the behavioral level, A-allele carriers showed pronounced fear reactivity prior to CBT which partially normalized afterwards. In sum, rs7688285 variation interacts in a complex manner with PD/AG on a functional systems level and might be involved in the development of PD/AG but not in their treatment.

2.
Acta Neuropsychiatr ; : 1-11, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31364522

RESUMO

OBJECTIVE: Despite its numerous side effects, clozapine is still the most effective antipsychotics making it an ideal reference substance to validate the efficacy of novel compounds for the treatment of schizophrenia. However, blood-brain barrier permeability for most new molecular entities is unknown, requiring central delivery. Thus, we performed a dose-finding study for chronic intracerebroventricular (icv) delivery of clozapine in mice. METHODS: Specifically, we implanted wild-type C57BL/6J mice with osmotic minipumps (Alzet) delivering clozapine at a rate of 0.15 µl/h at different concentrations (0, 3.5, 7 and 14 mg/ml, i.e. 0, 12.5, 25 and 50 µg/day). Mice were tested weekly in a modified SHIRPA paradigm, for locomotor activity in the open field and for prepulse inhibition (PPI) of the acoustic startle response (ASR) for a period of 3 weeks. RESULTS: None of the clozapine concentrations caused neurological deficits or evident gross behavioural alterations in the SHIRPA paradigm. In male mice, clozapine had no significant effect on locomotor activity or PPI of the ASR. In female mice, the 7 and 14 mg/ml dose of clozapine significantly affected both open field activity and PPI, while 3.5 mg/ml of clozapine increased PPI but had no effects on locomotor activity. CONCLUSION: Our findings indicate that 7 mg/ml may be the optimal dose for chronic icv delivery of clozapine in mice, allowing comparison to screen for novel antipsychotic compounds.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31422473

RESUMO

Depression and anxiety are common in childhood and adolescence. Even though cardinal symptoms differ, there is a considerable overlap regarding the pathogenic influence of serotonergic innervation, negative life experience, disturbed emotion perception/affect regulation, and impaired neural functioning in the fronto-limbic circuit. In this study, we examined the effect of the 5-HTTLPR/rs25531 genotype on depressive symptoms and trait anxiety under the consideration of the amount of negative life events in healthy children and adolescents (N = 389). In a subsample of 49 subjects, we performed fMRI to add fronto-limbic brain activation as a second interacting factor. Across all subjects, negative life events moderated the influence of the 5-HTTLPR/rs25531 genotype on both depressive symptoms and trait anxiety. In the fMRI subsample, 5-HTTLPR/rs25531 S + S/LG + S/LA + LGLA + LGLG genotype-associated left middle frontal gyrus (MFG) activation mediated the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms, however, only in combination with negative life events. Genetic influence on trait anxiety was predominantly mediated by negative life events; only LALA genotype-specific activation in the right MFG worked as a mediator in combination with negative life events. The present findings hint towards distinct mechanisms mediating the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms and anxiety, with negative life events playing a crucial role in both phenotypes. With regard to depressive symptoms, however, this influence was only visible in combination with MFG activation, whereas, in anxiety, it was independent of brain activation.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31405541

RESUMO

Nitric oxide signalling has been implicated in impulsive and aggressive traits and behaviours in both animals and humans. In the present study, we investigated the effects of a functional variable number of tandem repeats (VNTR) polymorphism in exon 1f (ex1f) of the nitric oxide synthase 1 (NOS1) gene (NOS1 ex1f-VNTR) and stressful life events on aggressive behaviour in population representative sample of adolescents followed up from third grade to 25 years of age. We studied the younger cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study (subjects in the last study wave n = 437, males n = 193; mean age 24.8 ± 0.5 years). Aggressive behaviour was rated at age 25 with the Illinois Bully Scale and Buss-Perry Aggression Questionnaire. Life history of aggression was evaluated in a structured interview. Stressful life events and family relationships were self-reported at age 15. The hypothesized risk genotype (homozygosity for the short allele) was associated with higher levels of aggression in males (statistical significance withstanding the multiple correction procedure). Exposure to stressful life events or adverse family relationships was associated with increased aggressive behaviour in subjects homozygous for either of the alleles, and these associations were mostly observed in males. However, these associations in these stratified analyses did not survive correction for multiple testing. Aggressiveness was relatively unaffected by the NOS1 ex1f-VNTR genotype in the female subjects even when taking exposure to childhood adversity into account. Our findings support the hypothesized involvement of a functional NOS1 polymorphism on aggression in a population representative sample of young adults.

5.
Nervenarzt ; 2019 Aug 12.
Artigo em Alemão | MEDLINE | ID: mdl-31407043

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common comorbidity in adult patients with substance use disorders (SUDs). The diagnostics and treatment of ADHD with SUD are often a challenge, also with respect to the prescription of stimulants. Recently, a group of international experts developed a consensus paper on the diagnosis and treatment of comorbid ADHD and SUD. In addition, the German S3 guidelines on ADHD have been published, which also give advice on the treatment of ADHD in comorbid SUD. The German S3 guidelines on alcohol-related disorders and methamphetamine-related disorders also address ADHD as a comorbidity. METHODS: Summary of consensus and guideline recommendations, supplemented with the most recent literature. CONCLUSION: In recent years new findings on the comorbidity of ADHD in patients with SUD have emerged. A series of screening and diagnostic instruments have meanwhile been evaluated in this patient group. The consensus paper and various guidelines therefore provide clinicians with specific help in detecting ADHD in patients with SUD and in conducting further diagnostics and treatment of both disorders. For example, the importance of stimulants in the treatment of patients with SUD and ADHD has significantly changed and first studies on psychotherapeutic interventions specific to this comorbidity are now available.

6.
Am J Psychiatry ; 176(8): 651-660, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164008

RESUMO

OBJECTIVE: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

7.
Brain Behav ; 9(6): e01257, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31066228

RESUMO

INTRODUCTION: Previous studies have established graph theoretical analysis of functional network connectivity (FNC) as a potential tool to detect neurobiological underpinnings of psychiatric disorders. Despite the promising outcomes in studies that examined FNC aberrancies in bipolar disorder (BD) and major depressive disorder (MDD), there is still a lack of research comparing both mood disorders, especially in a nondepressed state. In this study, we used graph theoretical network analysis to compare brain network properties of euthymic BD, euthymic MDD and healthy controls (HC) to evaluate whether these groups showed distinct features in FNC. METHODS: We collected resting-state functional magnetic resonance imaging (fMRI) data from 20 BD patients, 15 patients with recurrent MDD as well as 30 age- and gender-matched HC. Graph theoretical analyses were then applied to investigate functional brain networks on a global and regional network level. RESULTS: Global network analysis revealed a significantly higher mean global clustering coefficient in BD compared to HC. We further detected frontal, temporal and subcortical nodes in emotion regulation areas such as the limbic system and associated regions exhibiting significant differences in network integration and segregation in BD compared to MDD patients and HC. Participants with MDD and HC only differed in frontal and insular network centrality. CONCLUSION: In conclusion, our findings indicate that a significantly altered brain network topology in the limbic system might be a trait marker specific to BD. Brain network analysis in these regions may therefore be used to differentiate euthymic BD not only from HC but also from patients with MDD.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31099984

RESUMO

KCNJ6, encoding a potassium channel subunit, regulates the excitability of dopaminergic neurons and is expressed in attention-deficit/hyperactivity disorder (ADHD)-relevant brain regions. As a potential ADHD risk gene, KCNJ6, therefore, may contribute to the endophenotypic variation of the disorder. The impact of two SNPs, rs7275707 and rs6517442, both located in the transcriptional control region of KCNJ6, on reporter gene expression was explored in cultured cells. The KCNJ6 variants were then tested for association with ADHD and personality traits in a family-based sample (165 affected children) and an adult case-control sample (450 patients, 426 controls). Furthermore, the genotypic influence on performance in an n-back task and a cued continuous performance test (cCPT) was investigated by electroencephalography recordings. Finally, rs6517442 function was assessed by a reward anticipation paradigm using functional magnetic resonance imaging. Different haplotypes of rs7275707 and rs6517442 significantly influenced KCNJ6 gene expression proving their functional relevance on the molecular level. In the family-based children sample rs7275707 was associated with ADHD (p = .038). Moreover, rs7275707 showed association with the personality trait of Reward Dependence (p = .031). In the ADHD group, both rs7275707 and rs6517442 influenced the Go-centroid location in the cCPT and the N200 amplitude in the n-back task. Furthermore, ventral striatal activation was impacted by rs6517442 during reward anticipation. Our data indicate that functional variants of KCNJ6 influence brain activity during reward-related and executive processes supporting the view of a differential, age-dependent modulatory impact of dopamine-related brain processes in ADHD risk.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31076914

RESUMO

Attention deficit/hyperactivity disorder (ADHD) has been associated with a higher risk for accidents and injuries, leading to increased mortality. The objective of this study was to identify the types and mechanisms of accidents in a group of adult trauma victims with self-reported ADHD compared to a control group, based on Adult ADHD Self-Report Scale Version 1.1 (ASRSv1.1). A semi-open/qualitative accident questionnaire was conducted with 116 recruited patients from three trauma surgery units. The adult ADHD (aADHD) group differed significantly from the control group in self-reported psychiatric co-morbidities (p = 0.012), regular psychotropic medication use (p = 0.005), other accidents in the past year (p = 0.002), substance use before the accident (p = 0.007), and overconfidence in relation to the accident (p = 0.033). Most interestingly, we found significantly greater subjective ratings for stress (p = 0.002) and stressful/pressurising events before the accident (p = 0.026) in the adult ADHD group, as well as for self-reported stress at the time when conducting the interview (p = 0.016). The data demonstrate that special attention should be paid to interventions in stress reduction and sufficient treatment of ADHD in terms of preventing accidents and injuries in aADHD. Therefore, we suggest, in addition to pharmaceutical therapy, the integration of stress-management and coping strategies into aADHD management.

10.
Transl Psychiatry ; 9(1): 150, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123309

RESUMO

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (rg ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h2SNP) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h2SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.

11.
Metabolism ; 95: 65-76, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954559

RESUMO

Changes of sphingolipid metabolism were suggested to contribute to the patho-etiology of major depression (MD) and bipolar disorder (BD). In a pilot study we assessed if lipid allostasis manifested in pathological plasma concentrations of bioactive lipids i.e. endocannabinoids, sphingolipids, ceramides, and lysophosphatidic acids. METHODS: Targeted and untargeted lipidomic analyses were performed according to GLP guidelines in 67 patients with unipolar or bipolar disorders (20-67 years, 36 male, 31 female) and 405 healthy controls (18-79 years, 142 m, 263 f), who were matched according to gender, age and body mass index. Multivariate analyses were used to identify major components, which accounted for the variance between groups and were able to predict group membership. RESULTS: Differences between MD and BP patients versus controls mainly originated from ceramides and their hexosyl-metabolites (C16Cer, C18Cer, C20Cer, C22Cer, C24Cer and C24:1Cer; C24:1GluCer, C24LacCer), which were strongly increased, particularly in male patients. Ceramide levels were neither associated with the current episode, nor with the therapeutic improvement of the Montgomery Åsberg Depression Rating Scale (MARDS). However, long-chain ceramides were linearly associated with age, stronger in patients than controls, and with high plasma levels of diacyl- and triacylglycerols. Patients receiving antidepressants had higher ceramide levels than patients not taking these drugs. There was no such association with lithium or antipsychotics except for olanzapine. CONCLUSION: Our data suggest that high plasma ceramides in patients with major depression and bipolar disorder are indicative of a high metabolic burden, likely aggravated by certain medications.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30929061

RESUMO

Preliminary evidence suggests that BDNF (brain derived neurotrophic factor) rs6265 genetic polymorphism, BDNF gene promotor methylation and BDNF serum levels might play an important role in the pathogenesis of affective disorders. As studies testing the BDNF system across molecular levels are sparse, this study aimed at investigating the BDNF val66met genotype, BDNF DNA methylation changes and peripheral BDNF serum levels in acute and remitted phases of MDD (major depressive disorder) and BD (bipolar disorder) and healthy controls. We found a significant difference of methylation levels at CpG site 1-1-1 and 3-1-1 between MDD and healthy controls (p < 0.003) with MDD patients showing significantly higher methylation levels. CpG 5-2-1 revealed a statistically significant difference between MDD and healthy controls and MDD and BD (p = 0.00003). Similar to the results of the methylation analysis a significant difference between MDD and healthy controls was found in BDNF serum levels (p = 0.002) with significantly lower BDNF serum levels in MDD compared to healthy controls. A difference between the samples from admission and discharge from hospital of both BDNF gene methylation and serum levels could not be detected in the present study and no influence of the BDNF val66met genotype on neither methylation nor BDNF serum level.

13.
Behav Brain Res ; 369: 111927, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31034851

RESUMO

Exposure to childhood adversity is associated with increased vulnerability to stress-related disorders in adulthood which has been replicated in rodent stress models, whereas environmental enrichment has been suggested to have beneficial effects. However, the exact neurobiological mechanisms underlying these environment influences on adult brain and behavior are not well understood. Therefore, we investigated the long-term effects of maternal separation (MS) or environmental enrichment (EE) in male and female CD1 mice. We found clear sex-specific effects, but limited influence of environmental manipulations, on adult behavior, fecal corticosterone metabolite (FCM) levels and stress- and plasticity related gene expression in discrete brain regions. In detail, adult females displayed higher locomotor activity and FCM levels compared to males and EE resulted in attenuation in both measures, but only in females. There were no sex- or postnatal manipulation-dependent differences in anxiety-related behaviors in either sex. Gene expression analyses revealed that adult males showed higher Fkbp5 mRNA levels in hippocampus, hypothalamus and raphe nuclei, and higher hippocampal Nos1 levels. Interestingly, MS elevated Nos1 levels in hippocampus but reduced Fkbp5 expression in hypothalamus of males. Finally, we also found higher Maoa expression in the hypothalamus of adult females, however no differences were observed in the expression levels of Bdnf, Crhr1, Nr3c1 and Htr1a. Our findings further contribute to sex-dependent differences in behavior, corticosterone and gene expression and reveal that the effects of postnatal manipulations on these parameters in outbred CD1 mice are limited.

14.
Neuropharmacology ; 156: 107557, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30849401

RESUMO

Adhesion G protein-coupled receptor L3 (ADGRL3, LPHN3) has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the characteristics of Adgrl3-deficient mice in multiple behavioural domains related to ADHD: locomotive activity, impulsivity, gait, visuospatial and recognition memory, sociability, anxiety-like behaviour and aggression. Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum. Adgrl3-/- mice show increased locomotive activity across all tests and subtle gait abnormalities. These mice also show impairments across spatial memory and learning domains, alongside increased levels of impulsivity and sociability with decreased aggression. However, these alterations were absent in Adgrl3+/- mice. Across all brain regions tested, the numbers of genes found to exhibit differential expression was relatively small, indicating a specific pathway of action, rather than a broad neurobiological perturbation. Gene-set analysis of differential expression in the PFC detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The Slc6a3 gene coding for the dopamine transporter was the most dysregulated gene in the PFC. Unexpectedly, several neurohormone/peptides which are typically only expressed in the hypothamalus were found to be dysregulated in the striatum. Our study further validates Adgrl3 constitutive knockout mice as an experimental model of ADHD while providing neuroanatomical targets for future studies involving ADGRL3 modified models. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

15.
Transl Psychiatry ; 9(1): 75, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718541

RESUMO

Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10-7), particularly in the female subsample (p = 9.8 × 10-9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10-4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.


Assuntos
Agorafobia , Aprendizagem da Esquiva/fisiologia , Cérebro/fisiopatologia , Terapia Cognitivo-Comportamental , Medo/fisiologia , Receptores de Orexina/genética , Avaliação de Resultados (Cuidados de Saúde) , Transtorno de Pânico , Adulto , Agorafobia/genética , Agorafobia/fisiopatologia , Agorafobia/terapia , Estudos de Casos e Controles , Cérebro/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/genética , Transtorno de Pânico/fisiopatologia , Transtorno de Pânico/terapia , Fenótipo , Adulto Jovem
16.
Eur Psychiatry ; 58: 38-44, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30802682

RESUMO

BACKGROUND: ADHD is a highly prevalent disease in childhood which often persists into adulthood, then co-occurring with common adult conditions. Especially for adult ADHD, little is known about the costs of ADHD and the additional costs of comorbid conditions. AIMS: To determine medical costs of ADHD and costs of comorbidities (mood, anxiety and substance use disorders, obesity), including their co-occurrence rates, stratified by age and gender. METHOD: Claims data from a German Statutory Health Insurance database with approximately four million member-records per year were analysed. A total of 25,300 prevalent ADHD patients were identified by means of an ICD-10 GM diagnosis of ADHD. A 1:1 age and gender adjusted reference group without ADHD diagnosis was randomly selected. Total health claims and health care costs related to ADHD were analysed, in addition to more targeted analyses of the occurrence and costs of pre-defined common comorbidities of, in particular, adult ADHD (SUD, mood and anxiety disorders, obesity). Outcomes were mean costs per patient and occurrence rates of comorbid conditions. Surplus costs of a comorbid condition in persons with ADHD relative to costs of this condition in persons without ADHD were calculated. Subgroup analyses were conducted based on age (0-12 years, 13-17 years, 18-30years, 30+ years) and gender. RESULTS: Patients with ADHD were €1500 more expensive annually than individuals without ADHD (p < 0.001). Main cost drivers were inpatient care, psychiatrists and psychotherapists. Mood, anxiety, substance use disorders and obesity were significantly more frequent in ADHD patients and additional costs resulting from the comorbid conditions amounted up to €2800. Costs were slightly higher in women than men and increased with age for both genders. In young adults (18-30 years) health care costs dropped notably, especially costs for the medical treatment of ADHD with stimulants and costs for psychiatrists, before rising again in the group of patients over 30 years who had higher comorbidity rates. CONCLUSIONS: Medical costs for ADHD are substantial, in part through frequently occurring comorbid conditions, and particularly in adulthood, and are likely to further accelerate in the coming years. A gap of care was found, starting with the transition age group of patients over 17 years, as indicated by reduced costs per person during young adulthood, as well as an overall strong drop in administrative prevalence. In the future, approaches to improve the situation of care and reduce costs at the same time, i.e. through managed care programmes, should be implemented and benefit from detailed knowledge on age and gender-specific cost-drivers.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/economia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Custos de Cuidados de Saúde/estatística & dados numéricos , Gastos em Saúde/estatística & dados numéricos , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Doença Crônica/economia , Doença Crônica/epidemiologia , Comorbidade , Análise de Dados , Feminino , Alemanha , Serviços de Saúde/economia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Saúde Pública/economia , Adulto Jovem
17.
Psychiatr Genet ; 29(3): 63-78, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30741787

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder. In recent years, genetic studies have revealed several risk gene variants associated with ADHD; however, these variants could only be partly replicated and are responsible for only a fraction of the whole heritability of ADHD estimated from family and twin studies. One factor that could potentially explain the 'missing heritability' of ADHD is that childhood and adult or persistent ADHD could be genetically distinct subtypes, which therefore need to be analyzed separately. Another approach to identify this missing heritability could be combining the investigation of both common and rare gene risk variants as well as polygenic risk scores. Finally, environmental factors are also thought to play an important role in the etiology of ADHD, acting either independently of the genetic background or more likely in gene-environment interactions. Environmental factors might additionally convey their influence by epigenetic mechanisms, which are relatively underexplored in ADHD. The aforementioned mechanisms might also influence the response of patients with ADHD to stimulant and other ADHD medication. We conducted a selective review with a focus on risk genes of childhood and adult ADHD, gene-environment interactions, and pharmacogenetics studies on medication response in childhood and adult ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Interação Gene-Ambiente , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Criança , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
18.
Artigo em Inglês | MEDLINE | ID: mdl-30758784

RESUMO

Gene-environment-development interactions are suggested to play a crucial role in psychiatric disorders. However, it is not clear if there are specific risk gene interactions with particular pre-, peri-, and postnatal risk factors for distinct disorders, such as adult attention-deficit-/hyperactivity disorder (aADHD) and bipolar disorder (BD). In this pilot study, the first aim was to investigate retrospective self-reports of pre-, peri-, and postnatal complications and risk factors from 126 participants (aADHD, BD, and healthy controls) and their mothers. The second aim was to investigate possible interaction between the previously published common risk gene variants of ADHD in the ADGRL3 (=LPHN3) gene (rs2305339, rs1397548, rs734644, rs1397547, rs2271338, rs6551665, and rs2345039) and shared risk gene variants of aADHD and BD in the DGKH gene (DGKH rs994856/rs9525580/rs9525584 GAT haplotype) and pre-, peri-, and postnatal risk factors in comparison to a healthy control group. After correction for multiple comparison, the following pre-, peri-, and postnatal risk factors remained statistically significant (p ≤ 0.0036) between healthy controls and ADHD and BD patients as one group: unplanned pregnancies, psychosocial stress of the mother during pregnancy, mode of delivery, shared decision-making regarding medical procedures during the delivery, perinatal bonding, number of crybabies, and quality of mother-child and father-child relationship. There were no significant environment-gene interactions. In our preliminary data, similar risk factors were found to be significantly associated with both disorders in comparison to healthy controls. However, larger and longitudinal studies and standardized and validated instruments to get a better understanding of the interaction of pre-, peri-, and postnatal complications and mental health in the offspring are needed.

19.
J Atten Disord ; : 1087054718822129, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30623719

RESUMO

OBJECTIVE: The DIRAS2 gene is associated with ADHD, but its function is largely unknown. Thus, we aimed to explore the genes and molecular pathways affected by DIRAS2. METHOD: Using short hairpin RNAs, we downregulated Diras2 in murine hippocampal primary cells. Gene expression was analyzed by microarray and affected pathways were identified. We used quantitative real-time polymerase chain reaction (qPCR) to confirm expression changes and analyzed enrichment of differentially expressed genes in an ADHD GWAS (genome-wide association studies) sample. RESULTS: Diras2 knockdown altered expression of 1,612 genes, which were enriched for biological processes involved in neurodevelopment. Expression changes were confirmed for 33 out of 88 selected genes. These 33 genes showed significant enrichment in ADHD patients in a gene-set-based analysis. CONCLUSION: Our findings show that Diras2 affects numerous genes and thus molecular pathways that are relevant for neurodevelopmental processes. These findings may further support the hypothesis that DIRAS2 is linked to etiological processes underlying ADHD.

20.
Acta Neuropsychiatr ; : 1-8, 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30561291

RESUMO

OBJECTIVE: There is accumulating evidence that the error-related negativity (ERN), an event-related potential elicited after erroneous actions, is altered in different psychiatric disorders and may help to guide treatment options. Thus, the ERN is a promising candidate as a psychiatric biomarker. Basic methodological requirements for a biomarker are that their measurements are standardised and reliable. The aim of the present study was to establish ERN acquisition in a reliable, time-efficient and patient-friendly way for use in clinical practice. METHODS: Healthy subjects performed a speeded Eriksen Flanker Task that increases the number of errors. In a test-retest design (N = 14) with two sessions separated by 28 days we assessed the reliability of the ERN. To ensure external validity, we aimed to replicate previously reported correlation patterns of ERN amplitude with (A) number of errors and (B) negative affect. In order to optimise the clinical use of the task, we determined to which extent the task can be shortened while keeping reliability >0.80. RESULTS: We found excellent reliability of the ERN (intraclass correlation coefficients = 0.806-0.947) and replicated ERN correlation patterns. The task can be halved to a patient-friendly length of 200 trials (recorded in 8 min) keeping reliability >0.80. CONCLUSIONS: The modified task provides reliable and efficient recording of the ERN, facilitating its use as a psychiatric biomarker.

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