Showing papers in "American Journal of Psychiatry in 2019"
TL;DR: The results suggest that early hypotheses about depression candidate genes were incorrect and that the large number of associations reported in the depression candidate gene literature are likely to be false positives.
Abstract: Objective:Interest in candidate gene and candidate gene-by-environment interaction hypotheses regarding major depressive disorder remains strong despite controversy surrounding the validity of prev...
388 citations
TL;DR: Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy and is supported by the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.
Abstract: Objective:About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients wi...
333 citations
TL;DR: In this article, a genome-wide association analysis was performed to identify genetic variants associated with alcohol use disorders, which are common conditions that have enormous social and economic consequences, such as high blood cholesterol, obesity, and heart disease.
Abstract: Objective:Alcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated wi...
259 citations
Radboud University Nijmegen1, Erasmus University Medical Center2, University of Southern California3, National Institutes of Health4, Oregon Health & Science University5, Autonomous University of Barcelona6, Polytechnic University of Valencia7, Hartford Hospital8, University of Groningen9, VU University Amsterdam10, University of São Paulo11, University of Melbourne12, RWTH Aachen University13, Harvard University14, VA Boston Healthcare System15, University of California, San Diego16, University of California, Irvine17, University of Cincinnati18, University of Würzburg19, University of Amsterdam20, Haukeland University Hospital21, University of Bergen22, New York University23, Trinity College, Dublin24, Norwegian University of Science and Technology25, University of Zurich26, University of Barcelona27, University of London28, University of Reading29, University of Brighton30, Heidelberg University31, Federal University of Rio de Janeiro32, University of Tübingen33, Erasmus University Rotterdam34, Russian National Research Medical University35, University Hospital of Lausanne36, Brighton and Sussex University Hospitals NHS Trust37, University of Sussex38, Monash University39, Deakin University40, ETH Zurich41, German Center for Neurodegenerative Diseases42, University of Regensburg43, Nathan Kline Institute for Psychiatric Research44, Goethe University Frankfurt45, VU University Medical Center46, Yale University47, Pompeu Fabra University48, State University of New York System49
TL;DR: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention.
Abstract: OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.
231 citations
TL;DR: These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression and further expand on optimizing administration to better translate the use of ketamine into clinical settings.
Abstract: Objective:Subanesthetic ketamine doses have been shown to have rapid yet transient antidepressant effects in patients with treatment-resistant depression, which may be prolonged by repeated adminis...
213 citations
TL;DR: CBD's potential to reduce cue-induced craving and anxiety provides a strong basis for further investigation of this phytocannabinoid as a treatment option for opioid use disorder.
Abstract: Objective:Despite the staggering consequences of the opioid epidemic, limited nonopioid medication options have been developed to treat this medical and public health crisis. This study investigate...
204 citations
TL;DR: It is demonstrated that a connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity and that correction of this breakdown amelioratesnegative symptom severity, supporting a novel network hypothesis for medication-refractory negative symptoms and suggesting that network manipulation may establish causal relationships between network markers and clinical phenomena.
Abstract: Objective:The interpretability of results in psychiatric neuroimaging is significantly limited by an overreliance on correlational relationships. Purely correlational studies cannot alone determine...
204 citations
TL;DR: High-frequency dTMS over the medial prefrontal cortex and anterior cingulate cortex significantly improved OCD symptoms and may be considered as a potential intervention for patients who do not respond adequately to pharmacological and psychological interventions.
Abstract: Objective:Obsessive-compulsive disorder (OCD) is a chronic and disabling condition that often responds unsatisfactorily to pharmacological and psychological treatments. Converging evidence suggests...
198 citations
TL;DR: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis, supporting the unification of Tourette’s syndrome and other tic disorders in future diagnostic schemata.
Abstract: Objective:Tourette’s syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette’s...
189 citations
University of Vermont1, University of Oregon2, University of Melbourne3, Icahn School of Medicine at Mount Sinai4, University of Barcelona5, Radboud University Nijmegen6, Yale University7, University of Cape Town8, National Institute on Drug Abuse9, Monash University10, Utrecht University11, Montreal Neurological Institute and Hospital12, King's College London13, Oregon Health & Science University14, University of Rochester15, University of Amsterdam16, University of Michigan17, University of Colorado Boulder18, Washington University in St. Louis19, University of California, Los Angeles20, Australian Catholic University21, University of Liverpool22, National Institutes of Health23, University of California, San Diego24, McGovern Institute for Brain Research25, Max Planck Society26, Leiden University27, Illawarra Health & Medical Research Institute28, VU University Medical Center29, QIMR Berghofer Medical Research Institute30, University of Utah31
TL;DR: The results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine.
Abstract: Objective: Although lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes. Method: Brain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings. Results: Lower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subjects. Conclusions: The results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine.
176 citations
King's College London1, Icahn School of Medicine at Mount Sinai2, SUNY Downstate Medical Center3, Aarhus University4, Lundbeck5, University of Queensland6, Queensland University of Technology7, Harvard University8, Charité9, Broad Institute10, Berkshire Healthcare NHS Foundation Trust11, Trinity College, Dublin12, University of Chicago13, NorthShore University HealthSystem14, University of Basel15, University Hospital of Basel16, University of Bonn17, Goethe University Frankfurt18, Nofer Institute of Occupational Medicine19, University of Melbourne20, University of Münster21, University of Liverpool22, Max Planck Society23, Martin Luther University of Halle-Wittenberg24, VU University Amsterdam25, Centre for Addiction and Mental Health26, Ludwig Maximilian University of Munich27, Statens Serum Institut28
TL;DR: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders.
Abstract: 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.
TL;DR: The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes.
Abstract: Objective:Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification t...
TL;DR: It is demonstrated that individual differences in large-scale neural networks contribute to variability in treatment outcomes for cocaine use disorder, and they identify specific abstinence networks that may be targeted in novel interventions.
Abstract: Objective:The authors sought to identify a brain-based predictor of cocaine abstinence by using connectome-based predictive modeling (CPM), a recently developed machine learning approach. CPM is a ...
TL;DR: People with schizophrenia and other psychoses experience cognitive decline after illness onset, but the magnitude of decline varies across cognitive functions, and healthy individuals with low IQ showed no evidence of decline, suggesting that a decline is specific to psychosis.
Abstract: Objective:Schizophrenia is associated with a marked cognitive impairment that is widely believed to remain stable after illness onset. Yet, to date, 10-year prospective studies of cognitive functio...
TL;DR: Patients with higher polygenic risk scores for schizophrenia tended to have less improvement with antipsychotic drug treatment, and PRS burden may have potential utility as a prognostic biomarker.
Abstract: Objective:Pharmacogenomic studies of antipsychotics have typically examined effects of individual polymorphisms. By contrast, polygenic risk scores (PRSs) derived from genome-wide association studi...
TL;DR: QEEG does not appear to be clinically reliable for predicting depression treatment response, as the literature is limited by underreporting of negative results, a lack of out-of-sample validation, and insufficient direct replication of previous findings.
Abstract: Objective:Reducing unsuccessful treatment trials could improve depression treatment. Quantitative EEG (QEEG) may predict treatment response and is being commercially marketed for this purpose. The ...
TL;DR: Beyond the role of cognition in vulnerability to substance use, the concurrent and lasting effects of adolescent cannabis use can be observed on important cognitive functions and appear to be more pronounced than those observed for alcohol.
Abstract: Objective:Alcohol and cannabis misuse are related to impaired cognition. When inferring causality, four nonexclusive theoretical models can account for this association: 1) a common underlying vuln...
TL;DR: Evidence for interactive effects of PRS and previously associated CNVs for risk for schizophrenia is found, and the results for large deletions and total CNV burden support an additive model.
Abstract: Objective:Both rare copy number variants (CNVs) and common single-nucleotide polymorphisms (SNPs) contribute to liability to schizophrenia, but their etiological relationship has not been fully elu...
TL;DR: Cariprazine was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.
Abstract: Objective:Cariprazine, a dopamine D3/D2 and 5-HT1A receptor partial agonist, was found to be effective in treating bipolar I depression in a previous phase 2 study. This phase 3 study further asses...
TL;DR: A modest therapeutic effect of olanzapine compared with placebo on weight in adult outpatients with anorexia nervosa is documented, as achieving change in weight is notoriously challenging in this disorder.
Abstract: Objective:This study evaluated the benefits of olanzapine compared with placebo for adult outpatients with anorexia nervosa.Methods:This randomized double-blind placebo-controlled trial of adult ou...
TL;DR: In >8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS, consistent with the rate observed in studies of DBS for other indications.
Abstract: Objective:Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an...
TL;DR: Although the results do not support the routine prescription of hypnotic medication for mitigating suicidal ideation in all depressed outpatients with insomnia, they suggest that coprescription of a hypnotic during initiation of an antidepressant may be beneficial in suicidal outpat patients, especially in patients with severe insomnia.
Abstract: Objective:The authors sought to determine whether targeted treatment of insomnia with controlled-release zolpidem (zolpidem-CR) in suicidal adults with insomnia would provide a reduction in suicida...
TL;DR: First-episode psychosis studies have established an evidentiary basis for considering a team-based, coordinated specialty approach as the standard of care for treating early psychosis, which has led to their global proliferation.
Abstract: Scientific progress in understanding human disease can be measured by the effectiveness of its treatment. Antipsychotic drugs have been proven to alleviate acute psychotic symptoms and prevent their recurrence in schizophrenia, but the outcomes of most patients historically have been suboptimal. However, a series of findings in studies of first-episode schizophrenia patients transformed the psychiatric field's thinking about the pathophysiology, course, and potential for disease-modifying effects of treatment. These include the relationship between the duration of untreated psychotic symptoms and outcome; the superior responses of first-episode patients to antipsychotics compared with patients with chronic illness, and the reduction in brain gray matter volume over the course of the illness. Studies of the effectiveness of early detection and intervention models of care have provided encouraging but inconclusive results in limiting the morbidity and modifying the course of illness. Nevertheless, first-episode psychosis studies have established an evidentiary basis for considering a team-based, coordinated specialty approach as the standard of care for treating early psychosis, which has led to their global proliferation. In contrast, while clinical high-risk research has developed an evidence-based care model for decreasing the burden of attenuated symptoms, no treatment has been shown to reduce risk or prevent the transition to syndromal psychosis. Moreover, the current diagnostic criteria for clinical high risk lack adequate specificity for clinical application. What limits our ability to realize the potential of early detection and intervention models of care are the lack of sensitive and specific diagnostic criteria for pre-syndromal schizophrenia, validated biomarkers, and proven therapeutic strategies. Future research requires methodologically rigorous studies in large patient samples, across multiple sites, that ideally are guided by scientifically credible pathophysiological theories for which there is compelling evidence. These caveats notwithstanding, we can reasonably expect future studies to build on the research of the past four decades to advance our knowledge and enable this game-changing model of care to become a reality.
TL;DR: iTBS appears to be a promising new treatment for PTSD, and neuroimaging indicated that clinical improvement was significantly predicted by stronger (greater positive) connectivity within the default mode network and by anticorrelated cross-network connectivity.
Abstract: Objective:Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. Transcranial magnetic stimulation (TMS) rep...
TL;DR: Following frustration, levels of irritability correlated with activity in neural systems mediating attention orienting, top-down regulation of emotions, and motor execution.
Abstract: Objective:Childhood irritability is a common, impairing problem with changing age-related manifestations that predict long-term adverse outcomes. However, more investigation of overall and age-spec...
TL;DR: Brain network architecture can explain the irregular topographic distribution of cortical thickness reductions in schizophrenia, and the finding that the effect is robust and independent of illness stage is suggested.
Abstract: Objective:Cortical thickness reductions in schizophrenia are irregularly distributed across multiple loci. The authors hypothesized that cortical connectivity networks would explain the distributio...
TL;DR: Prolonged exposure and sertraline confer significant benefits for PTSD, with some evidence of an advantage for prolonged exposure.
Abstract: Objective:The authors examined the effect of patient treatment preference on the differential effectiveness of prolonged exposure and sertraline for the treatment of posttraumatic stress disorder (...
TL;DR: Bipolar disorder in individuals at familial risk typically unfolds in a progressive clinical sequence, and childhood sleep and anxiety disorders are important predictors, as are clinically significant mood symptoms and psychotic symptoms in depressive episodes.
Abstract: Objective:The authors sought to describe the emergent course of bipolar disorder in offspring of affected parents subgrouped by parental response to lithium prophylaxis.Methods:Parent bipolar disor...
Radboud University Nijmegen1, Utrecht University2, Harvard University3, Broad Institute4, Aarhus University5, Lundbeck6, University of North Carolina at Chapel Hill7, University of Southern California8, Erasmus University Rotterdam9, University of Toronto10, King's College London11, University of Würzburg12, Karolinska Institutet13, Stockholm County Council14, QIMR Berghofer Medical Research Institute15, State University of New York Upstate Medical University16, University of Bergen17
TL;DR: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level.
Abstract: Objective:Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the n...
TL;DR: Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol, and raise the possibility of developing individualized treatment protocols.
Abstract: Objective:Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. Th...