From genetics to biology: advancing mental health research in the Genomics ERA.

The Genomics Workgroup of the National Advisory Mental Health Council (NAMHC) recently issued a set of recommendations for advancing the NIMH psychiatric genetics research program and prioritizing subsequent follow-up studies. The report emphasized the primacy of rigorous statistical support from properly designed, well-powered studies for pursuing genetic variants robustly associated with disease. Here we discuss the major points NIMH program staff consider when assessing research applications based on common and rare variants, as well as genetic syndromes, associated with psychiatric disorders. These are broad guiding principles for investigators to consider prior to submission of their applications. NIMH staff weigh these points in the context of reviewer comments, the existing literature, and current investments in related projects. Following the recommendations of the NAMHC, statistical strength and robustness of the underlying genetic discovery weighs heavily in our funding considerations as does the suitability of the proposed experimental approach. We specifically address our evaluation of applications motivated in whole, or in part, by an association between human DNA sequence variation and a disease or trait relevant to the mission of the NIMH.

NIMH perspectives on future directions in neuroimaging for mental health.

NIMH's mission is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. New imaging techniques hold great promise for improving our understanding of the pathophysiology of mental illnesses, stratifying patients for treatment selection, and developing a personalized medicine approach. Here, we highlight emerging and promising new technologies that are likely to be vital in helping NIMH accomplish its mission, the potential for utilizing multimodal approaches to study mental illness, and considerations for data analytics and data sharing.

New directions in psychiatric drug development: promising therapeutics in the pipeline.

INTRODUCTION: Psychiatric disorders are a leading cause of disability worldwide, calling for an urgent need for new treatments, early detection, early intervention, and precision medicine. Drug discovery and development in psychiatry continues to expand in new and exciting areas, with several new medications approved for psychiatric indications by the U.S. Food and Drug Administration (FDA) in the last 5 years. AREAS COVERED: In this review, the authors summarize recent new drug approvals and new molecular mechanisms in Phase 1-3 clinical development for psychiatric disorders. Advances in human genetics-driven target identification, emergent technologies such as artificial intelligence-enabled drug discovery, digital health technologies, and biomarker tools and strategies for testing novel mechanisms are highlighted. EXPERT OPINION: There continues to be a need for research focused on understanding the natural history, developmental trajectory, and pathophysiology of psychiatric disorders to identify new molecular and circuit-based targets. Looking to the future, a vision of precision psychiatry is emerging, taking advantage of advances in genetics, digital technology, and multimodal biomarkers to accelerate the development of next-generation therapies for individuals living with mental illnesses.

Development of an evidence-based clinical practice guideline on linear growth measurement of children.

Growth is an important indicator of child health; however, measurements are frequently inaccurate and unreliable. This article reviews the literature on linear growth measurement error and describes methods used to develop and evaluate an evidence-based clinical practice guideline on the measurement of recumbent length and stature of infants, children, and adolescents. Systematic methods were used to identify evidence to answer clinical questions about growth measurement. A multidisciplinary team critically appraised and synthesized the evidence to develop clinical practice recommendations using an evidence-based practice rating scheme. The guideline was prospectively evaluated through internal and external reviews and a pilot study to ensure its validity and reliability. Adoption of the clinical practice guideline can improve the accuracy and reliability of growth measurement data.

New paradigms for treatment development.

Wayne Fenton believed that government-particularly National Institute of Mental Health (NIMH)-could play a critical role in addressing important public health problems where the current system of treatment development was inadequate. Earlier experiences in HIV/AIDS convinced him and others that the NIMH can effectively facilitate the rapid development of new research in critical areas. This report will demonstrate how the work of Fenton and others brought together representatives from industry, government, and academia to address issues that included new preclinical approaches to drug development and defining new therapeutic targets in schizophrenia. An initiative to facilitate the development of new pharmacological agents to address the cognitive impairments in schizophrenia-titled Measurement and Treatment Research to Improve Cognition in Schizophreniaor MATRICS-is used as an example of a new paradigm for treatment development.

What evidence do we need for biomarker qualification?

Biomarkers can facilitate all aspects of the drug development process. However, biomarker qualification-the use of a biomarker that is accepted by the U.S. Food and Drug Administration-needs a clear, predictable process. We describe a multistakeholder effort including government, industry, and academia that proposes a framework for defining the amount of evidence needed for biomarker qualification. This framework is intended for broad applications across multiple biomarker categories and uses.

Developing novel treatments for mood disorders: accelerating discovery.

This review was generated from discussions by the Pharmacologic and Somatic Treatments Section of the National Institute of Mental Health Strategic Plan for Mood Disorders Committee on advancing novel pharmacologic and somatic treatments for mood disorders. The opening section of the article summarizes in broad strokes, current pharmacologic treatments, and new directions in the field. Thereafter the topics focus on specific research initiatives that could advance the current therapeutics for mood disorders including new basic and clinical research in vivo human imaging procedures, somatic therapeutics, and the vast new area of pharmacogenetics. New scientific and technical opportunities exist today based on advances in basic neuroscience, opportunities in clinical testing, industry interest in advancing central nervous system therapeutics, and on active consumer advocacy groups. The question of how to bring all of these positive forces together to accelerate discovery in mood disorder thera-peutics is the topic of this article.

Enhancement of dynorphin gene expression in spinal cord following experimental inflammation: stimulus specificity, behavioral parameters and opioid receptor binding.

The stimulus specificity for enhancement of dynorphin gene expression in rat spinal cord was studied by combined measurements of the peptide dynorphin A 1-8 and preprodynorphin mRNA levels during peripheral inflammation induced by several agents. The density of kappa receptors, the putative receptor for dynorphin peptides, was examined using receptor binding with autoradiographic visualization. Mu and delta receptor classes were also studied. All inflammatory agents tested (carrageenan, phorbol ester, yeast and Freund's adjuvant) rapidly induced edema and thermal hyperalgesia. All agents also induced a rapid (within 8 h) elevation in dynorphin mRNA and, in comparison, a delayed (within 2 days) elevation of dynorphin A 1-8 peptide; peak peptide levels were reached at 4 days. No alteration of kappa, mu or delta receptor binding was observed at 4 h or 4 days post inflammation. The rapid development of thermal hyperalgesia and elevation of dynorphin mRNA and peptide content indicates that the involvement of dynorphin-containing neurons in nociceptive processing does not require a chronic abnormality and a dynamic picture of opioid modulation of sensory processing emerges. These data also demonstrate that activation of dynorphin biosynthesis in spinal cord is a feature common to hyperalgesia and peripheral inflammation and is not restricted to any one type of inflammatory agent. The lack of alteration in receptors suggests that the physiological effects of an increased biosynthesis are not accompanied by a concurrent down-regulation of opiate receptors.

Prophylactic feeding of Lactobacillus acidophilus NCFM to mice attenuates overt colonic hyperplasia.

The objective of this project was to determine if the probiotic Lactobacillus acidophilus NCFM would protect mice from developing transmissible murine colonic hyperplasia (TMCH) caused by Citrobacter rodentium. Our hypothesis was that the oral administration of L. acidophilus NCFM to mice would mitigate colonic hyperplasia and modulate the host immune response. A concurrent administration (CA) study was performed by feeding mice phosphate-buffered saline (PBS), C. rodentium only, L. acidophilus NCFM only, or C. rodentium and NCFM concurrently on the same day. The mice in the CA study were not protected by the probiotic, since their mean colon sample weights (0.109 g) were significantly higher than those of the PBS controls (0.0774 g), and the hematoxylin and eosin-stained samples showed histological changes typically associated with TMCH. A prophylactic feeding (PF) study was performed by orally feeding mice PBS or NCFM once daily for 20 consecutive days; in addition, on day 7, mice were challenged with either PBS or C. rodentium. Mice in the PF study were protected when they consumed the probiotic prior to the pathogen challenge, since their mean colon sample weights (0.0812 g) were not significantly higher than those of the controls (0.0753 g). The hematoxylin and eosin-stained samples appeared similar to the control samples, and the intestinal interleukin (IL)-15 and gamma interferon (IFN-gamma) mRNA levels were reduced. L. acidophilus NCFM did attenuate overt colonic hyperplasia when fed to mice prior to challenge with C. rodentium. The mouse model used in this study enabled us to investigate the efficacy of the L. acidophilus NCFM in preventing gastrointestinal disease and is a valid model for future probiotic research.

A survey of compliance: Medicaid's mandated blood lead screenings for children age 12-18 months in Nebraska.

BACKGROUND: To determine the frequency of Medicaid mandated blood lead level (BLL) screening compliance rates by clinical site. METHODS: Retrospective chart review for evidence of BLLs. Data analyses were conducted using frequencies, percentages & chi-square. RESULTS: The overall incidence of documented BLLs was 78.9% with one clinic demonstrating 100% BLLs while the others had 72%. Screening rates differed significantly by clinical site (X2 = 18.460, df = 3, p < 0.001). CONCLUSION: Although universal blood lead screening is mandated, there were missed opportunities to obtain BLLs in 21.1% of the records reviewed. Only one clinic had 100% documentation of BLLs when children on Medicaid were seen between the ages of 12-18 months.

Public-private partnerships to revitalize psychiatric drug discovery.

INTRODUCTION: Precompetitive public-private partnerships (PPPs) have the potential to improve psychiatric drug discovery by addressing gaps in the research and development pipeline such as the identification and validation of new targets, models, biomarkers and disease phenotyping. PPPs are a model to strategically bring together expertise, in-kind support and funding from multiple public and private sector partners. AREAS COVERED: This editorial describes selected case examples of established and emerging public-private consortia in the United States and Europe that provide tools, methods or resources to accelerate central nervous system (CNS) drug discovery. The authors provides a listing of public-private consortia projects that focus on the CNS, the stage of the drug discovery pipeline that they address, diseases, deliverables provided and current consortia partners. EXPERT OPINION: Some of the projects undertaken by PPPs in the area of CNS drug discovery and development are beginning to make tools, resources and data publicly available. Only a few PPPs have delivered enough to extract lessons learned. These include building alignment across a wide group of stakeholders, engaging advocacy groups and funding commitments for a minimum of 5 years.

Medicines for the mind: policy-based "pull" incentives for creating breakthrough CNS drugs.

Several large pharmaceutical companies have selectively downsized their neuroscience research divisions, reflecting a growing view that developing drugs to treat brain diseases is more difficult and often more time-consuming and expensive than developing drugs for other therapeutic areas, and thus represents a weak area for investment. These withdrawals reduce global neuroscience translational capabilities and pose a serious challenge to society's interests in ameliorating the impact of nervous system diseases. While the path forward ultimately lies in improving understandings of disease mechanisms, many promising therapeutic approaches have already been identified, and rebalancing the underlying risk/reward calculus could help keep companies engaged in making CNS drugs. One way to do this that would not require upfront funding is to change the policies that regulate market returns for the most-needed breakthrough drugs. The broader neuroscience community including clinicians and patients should convene to develop and advocate for such policy changes.

Assessing biomarkers for brain diseases: progress and gaps.

A report on the 2nd Wellcome Trust Scientific Conference on Biomarkers for Brain Disorders: Challenges and Opportunities, held at the Moller Centre, Cambridge, UK, February 3-5, 2013.