[Show abstract][Hide abstract] ABSTRACT: Purpose of review:
The recent explosion of genetic findings in autism spectrum disorder (ASD) research has improved knowledge of the disorder's underlying biology and etiologic architecture. This review introduces concepts and results from recent genetic studies and discusses the manner in which those findings can influence the trajectory of ASD research.
Large consortium studies have associated ASDs with many types of genetic risk factors, including common polygenic risk, de novo single nucleotide variants, copy number variants, and rare inherited variants. In aggregate, these results confirm the heterogeneity and complexity of ASDs. The rare variant findings in particular point to genes and pathways that begin to bridge the gap between behavior and biology.
Genetic studies have the potential to identify the biological underpinnings of ASDs and other neuropsychiatric disorders. The data they generate are already being used to examine disease pathways and pathogenesis. The results also speak to ASD heterogeneity and, in the future, may be used to stratify research studies and treatment trials.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.
Preview · Article · Sep 2015 · Current opinion in pediatrics
[Show abstract][Hide abstract] ABSTRACT: Mental disorders have high aggregate prevalence, are responsible globally for nearly a quarter of all years lived with disability, and represent the largest cause of lost economic output among all classes of noncommunicable disease worldwide. Cost-effective treatments, including both generic drugs and brief, manualized cognitive therapies are available to address this burden. Nonetheless, treatment of mental disorders remains a low priority worldwide-disproportionately so in low- and middle-income countries. Here, I focus on possible reasons for the failure of policy-makers to respond effectively, and I suggest corrective approaches.
Preview · Article · Sep 2014 · Science translational medicine
[Show abstract][Hide abstract] ABSTRACT: In the face of growing controversy about the utility of genetic mouse models of human disease, Rothwell et al. report on a shared mechanism by which two different neuroligin-3 mutations, associated with autism spectrum disorders in humans, produce an enhancement in motor learning. The open question is how much we can learn about human ills from such models.
[Show abstract][Hide abstract] ABSTRACT: Genetic analysis is currently offering glimpses into molecular mechanisms underlying such neuropsychiatric disorders as schizophrenia, bipolar disorder and autism. After years of frustration, success in identifying disease-associated DNA sequence variation has followed from new genomic technologies, new genome data resources, and global collaborations that could achieve the scale necessary to find the genes underlying highly polygenic disorders. Here we describe early results from genome-scale studies of large numbers of subjects and the emerging significance of these results for neurobiology.
No preview · Article · Jun 2014 · Nature Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Despite high prevalence and enormous unmet medical need, the pharmaceutical industry has recently de-emphasized neuropsychiatric disorders as 'too difficult' a challenge to warrant major investment. Here I describe major obstacles to drug discovery and development including a lack of new molecular targets, shortcomings of current animal models, and the lack of biomarkers for clinical trials. My major focus, however, is on new technologies and scientific approaches to neuropsychiatric disorders that give promise for revitalizing therapeutics and may thus answer industry's concerns.
No preview · Article · Jan 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Advances in genome analysis, accompanied by the assembly of large patient cohorts, are making possible successful genetic analyses of polygenic brain disorders. If the resulting molecular clues, previously hidden in the genomes of affected individuals, are to yield useful information about pathogenesis and inform the discovery of new treatments, neurobiology will have to rise to many difficult challenges. Here we review the underlying logic of the genetic investigations, describe in more detail progress in schizophrenia and autism, and outline the challenges for neurobiology that lie ahead. We argue that technologies at the disposal of neuroscience are adequately advanced to begin to study the biology of common and devastating polygenic disorders.
[Show abstract][Hide abstract] ABSTRACT: Neuroscience studies into psychiatric disorders generally rely on disease definitions that are based on the influential Diagnostic and Statistical Manual of Mental Disorders (DSM), the fifth edition of which (DSM-5) was released earlier this year. Designed as a purely diagnostic tool, the DSM considers different disorders as distinct entities. However, boundaries between disorders are often not as strict as the DSM suggests. To provide an alternative framework for research into psychiatric disorders, the US National Institute of Mental Health (NIMH) has recently introduced its Research Domain Criteria (RDoC) project. In the RDoC, five 'domains' each reflect a brain system in which functioning is impaired, to different degrees, in different psychiatric conditions. Nature Reviews Neuroscience asked six leading investigators for their thoughts on how DSM-5 and the RDoC will influence neuroscience research into psychiatric disorders.
Full-text · Article · Oct 2013 · Nature Reviews Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Editor’s note:
Although one in five Americans currently takes at least one psychiatric drug and mental disorders are recognized worldwide, global pharmaceutical industry funding for new, innovative medications is in serious decline despite promising advances in genetics. The author traces the evolution of psychiatric drug development, the reasons for its retreat, and the changes necessary to meet the growing demand.
Preview · Article · Apr 2013 · Cerebrum: the Dana forum on brain science
[Show abstract][Hide abstract] ABSTRACT: Drug discovery is at a near standstill for treating psychiatric disorders such as schizophrenia, bipolar disorder, depression, and common forms of autism. Despite high prevalence and unmet medical need, major pharmaceutical companies are deemphasizing or exiting psychiatry, thus removing significant capacity from efforts to discover new medicines. In this Commentary, I develop a view of what has gone wrong scientifically and ask what can be done to address this parlous situation.
Preview · Article · Oct 2012 · Science translational medicine
[Show abstract][Hide abstract] ABSTRACT: A report in this issue suggests that inhibiting histone deacetylase 2 (HDAC2) could be therapeutic in schizophrenia. Targeting chromatin remodeling in adults to treat a chronic brain disorder is not, however, likely to be easy.
No preview · Article · Aug 2012 · Nature Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Stimulants have been shown to be safe and effective for reduction of the symptoms of attention deficit hyperactivity disorder. Despite much debate, however, there has been little empirical evidence as to whether stimulants affect authenticity and moral agency in children. Singh presents evidence that stimulants do not undercut children's' sense of self and increase their experience of agency. These findings are consistent with laboratory evidence that stimulant drugs in therapeutic doses improve cognitive control over thought and behavior.
Preview · Article · May 2012 · Journal of Medical Ethics