Better Approaches to Derisking Psychiatric Drug Development are Needed, Not New Funding Mechanisms.

BACKGROUND: The pulling back of large pharma from psychiatric drug development over the last 15 years has been a cause of concern. The uncertainty of success with any novel mechanism raises questions concerning whether current funding mechanisms for the various components of drug development need to be revisited. Alternatively, advances in neuroscience and translational methods may provide a sufficient incentive for continued private sector investment. METHOD: Narrative commentary drawing on personal positions in both NIH and Industry devoted to translation of CNS compounds from bench to bedside coupled with specific examples of efforts to improve the selection of compounds to take into large clinical trials. RESULTS: Strategies for increasing R&D productivity in the field of CNS drugs articulated over a decade ago have been implemented over the same period with pre-competitive consortia involved in developing the tools needed to show that before being taken into large trials adequate evidence of postulated brain effects are required. In parallel, the field and the FDA have focused much more on the search for domain specific treatments rather than those depending on traditional measures of efficacy in DSM disorders. NIMH programs such as RDoC and the "Fast-Fail" initiative are provided as efforts which influence and involve partnerships with industry. CONCLUSIONS: The evolution of the field over the last decade is such that there is a shared focus across sources of funding in the public sector, especially NIH brain institutes, on the tools needed to de-risk psychiatric drug development to the degree needed to encourage private sector investment in the clinical trials needed to advance potential new treatments for areas of greatest need. Expansion of funding for translational tool development will have the highest impact on delivering novel treatments.

Central Nervous System Trial Failures: Using the Fragile X Syndrome-mGluR5 Drug Target to Highlight the Complexities of Translating Preclinical Discoveries Into Human Trials.

PURPOSE/BACKGROUND: Drug trials of the central nervous system(CNS) have been plagued with uninformative failures, often because of the difficulties of knowing definitively whether dosing achieved was sufficient to modulate the intended CNS target at adequate concentrations to produce pharmacodynamic or dose-related changes in readouts of brain function. Key design elements can be introduced into early-stage trials to get at this issue. METHODS/PROCEDURES: This commentary builds on a review of earlier clinical studies in Fragile X syndrome to explore the extent to which the chain of evidence is in place to allow for interpretation of the results as ruling in or out the utility of modulating one or another molecular target to treat this disorder. Recent and current biomarker studies in Fragile X syndrome occurring subsequent to the clinical studies are reviewed to see if they might address any chain of evidence gaps. FINDINGS/RESULTS: Despite the strong preclinical basis for targeting molecular mechanisms, the lack of efficacy seen in clinical studies remains uninterpretable, with regard to ruling in or out the utility of targeting the mechanism in a clinical population, given the absence of studies, which address whether doses of administered drug impacted the targeted brain mechanism. IMPLICATIONS/CONCLUSIONS: The value of pursuing clinical studies of compounds targeted to novel mechanisms in the absence of clinical pharmacological evidence of some anticipated mediating pharmacokinetic/pharmacodynamic signals is questionable. One or more biomarkers of a drug effect on brain function are needed to establish dose dependent CNS effects that allow one to interpret clinical results as ruling in or out a mechanism and providing a firm basis for continuing or not, as well as informing dose selection in any clinical efficacy trials. Initiatives to address this general need in pediatric psychopharmacology are highlighted.

Comparative analytical performance of multiple plasma Aß42 and Aß40 assays and their ability to predict positron emission tomography amyloid positivity.

INTRODUCTION: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aß) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. METHODS: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aß assays. Statistical tests were performed to determine whether the plasma Aß measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. RESULTS: The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). DISCUSSION: Measurement of Aß in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. HIGHLIGHTS: The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aß) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aß42/40 predicted amyloid positron emission tomography status better than Aß42 or Aß40 alone.

Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states.

There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N = 23) or decreased (N = 31) appetite and weight in their current depressive episode and healthy control participants (N = 42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.

Longitudinal CSF proteomics identifies NPTX2 as a prognostic biomarker of Alzheimer's disease.

INTRODUCTION: Biomarkers that reflect pathologic processes affecting neuronal function during preclinical and early stages of Alzheimer's disease (AD) are needed to aid drug development. METHODS: A targeted, stable isotope, quantitative mass spectrometry-based investigation of longitudinal changes in concentrations of previously identified candidate biomarkers was performed in cerebrospinal fluid (CSF) of Alzheimer's Disease Neuroimaging Initiative participants who were classified as cognitively normal (CN; n = 76) or with mild cognitive impairment (MCI; n = 111) at baseline. RESULTS: Of the candidate biomarkers, the CSF concentration of neuronal pentraxin 2 (NPTX2), a protein involved in synaptic function, exhibited rates of change that were significantly different between three comparison groups (i.e., CN vs. MCI participants; AD pathology positive vs. negative defined by phosphorylated tau181/amyloid beta1-42 ratio; and clinical progressors vs. non-progressors). The rate of change of NPTX2 also significantly correlated with declining cognition. DISCUSSION: CSF NPTX2 concentration is a strong prognostic biomarker candidate of accelerated cognitive decline with potential use as a therapeutic target.

Surprises in astrophysical gasdynamics.

Much of astrophysics consists of the study of ionized gas under the influence of gravitational and magnetic fields. Thus, it is not possible to understand the astrophysical universe without a detailed knowledge of the dynamics of magnetized fluids. Fluid dynamics is, however, a notoriously tricky subject, in which it is all too easy for one's a priori intuition to go astray. In this review, we seek to guide the reader through a series of illuminating yet deceptive problems, all with an enlightening twist. We cover a broad range of topics including the instabilities acting in accretion discs, the hydrodynamics governing the convective zone of the Sun, the magnetic shielding of a cooling galaxy cluster, and the behaviour of thermal instabilities and evaporating clouds. The aim of this review is to surprise and intrigue even veteran astrophysical theorists with an idiosyncratic choice of problems and counterintuitive results. At the same time, we endeavour to bring forth the fundamental ideas, to set out important assumptions, and to describe carefully whatever novel techniques may be appropriate to the problem at hand. By beginning at the beginning, and analysing a wide variety of astrophysical settings, we seek not only to make this review suitable for fluid dynamic veterans, but to engage novice recruits as well with what we hope will be an unusual and instructive introduction to the subject.

Perspective: The Alzheimer's Disease Neuroimaging Initiative and the role and contributions of the Private Partner Scientific Board (PPSB).

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partner Scientific Board (PPSB) is comprised of representatives of private, for-profit entities (including pharmaceutical, biotechnology, diagnostics, imaging companies, and imaging contract research organizations), and nonprofit organizations that provide financial and scientific support to ADNI through the Foundation for the National Institutes of Health. The PPSB serves as an independent, open, and precompetitive forum in which all private sector and not-for-profit partners in ADNI can collaborate, share information, and offer scientific and private-sector perspectives and expertise on issues relating to the ADNI project. In this article, we review and highlight the role, activities, and contributions of the PPSB within the ADNI project, and provide a perspective on remaining unmet needs and future directions.

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease.

With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

Finding new and better treatments for psychiatric disorders.

In contrast to most fields of medicine, progress to discover and develop new and improved psychiatric drugs has been slow and disappointing. The vast majority of currently prescribed drugs to treat schizophrenia, mood and anxiety disorders are arguably no more effective than the first generation of psychiatric drugs introduced well over 50 years ago. With only a few exceptions current psychiatric drugs work via the same fundamental mechanisms of action as first-generation agents. Here we describe the reasons for this slow progress and outline a number of areas of research that involve a greater reliance on experimental therapeutics utilizing recent advances in neuroscience to better understand disease biology. We exemplify the potential impact of these areas of research focus with several recent examples of novel agents that have emerged and which support our optimism that newer, more effective and better tolerated agents, are on the horizon. Together with existing drugs these newer agents and novel mechanisms could offer markedly improved functional outcomes for the millions of people still disabled by psychiatric disorders.

Head-to-head comparison of leading blood tests for Alzheimer's disease pathology.

INTRODUCTION: Blood tests have the potential to improve the accuracy of Alzheimer disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes. METHODS: Plasma samples from the Alzheimers Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes. RESULTS: Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes. DISCUSSION: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes.

A primary microcephaly-associated sas-6 mutation perturbs centrosome duplication, dendrite morphogenesis, and ciliogenesis in Caenorhabditis elegans.

The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear. The SASS6(I62T) mutation corresponds to SAS-6(L69T) in Caenorhabditis elegans. Given that SAS-6 is highly conserved, we modeled this mutation in C. elegans and examined the sas-6(L69T) effect on centrosome duplication, ciliogenesis, and dendrite morphogenesis. Our studies revealed that all the above processes are perturbed by the sas-6(L69T) mutation. Specifically, C. elegans carrying the sas-6(L69T) mutation exhibit an increased failure of centrosome duplication in a sensitized genetic background. Further, worms carrying this mutation also display shortened phasmid cilia, an abnormal phasmid cilia morphology, shorter phasmid dendrites, and chemotaxis defects. Our data show that the centrosome duplication defects caused by this mutation are only uncovered in a sensitized genetic background, indicating that these defects are mild. However, the ciliogenesis and dendritic defects caused by this mutation are evident in an otherwise wild-type background, indicating that they are stronger defects. Thus, our studies shed light on the novel mechanisms by which the sas-6(L69T) mutation could contribute to the incidence of primary microcephaly in humans.

Shifting the trajectory of therapeutic development for neurological and psychiatric disorders.

Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric disorders. Greater efforts must be centered on rigorously standardizing data collection and sharing of methods, datasets, and analytical tools across sectors. To address health care disparities in clinical trials, diversity of genetic ancestries and environmental exposures of research participants and associated biological samples must be prioritized.

Using latent profile analyses to classify subjects with anhedonia based on reward-related measures obtained in the FAST-MAS study.

BACKGROUND: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments. METHODS: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures. RESULTS: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures. LIMITATIONS: The main limitations include the small sample size and exploratory nature of analyses. CONCLUSIONS: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity.

A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder.

Converging lines of evidence suggest that the glutamatergic system may play an increasingly important role in the development of novel therapeutics for major depressive disorder (MDD), particularly agents associated with rapid antidepressant effects. Diverse glutamatergic modulators targeting N-methyl-D-aspartate receptors have shown efficacy in MDD, but their associated psychotomimetic effects presently preclude their use in larger samples. This small, randomized, double-blind, placebo-controlled, crossover pilot study evaluated the potential antidepressant efficacy and tolerability of an oral formulation of the selective N-methyl-D-aspartate NR2B antagonist MK-0657 in patients with treatment-resistant MDD (TRD). The TRD subjects underwent a 1-week drug-free period and were subsequently randomized to receive either MK-0657 monotherapy (4-8 mg/d) or placebo for 12 days. Because of recruitment challenges and the discontinuation of the compound's development by the manufacturer, only 5 of the planned 21 patients completed both periods of the crossover administration of MK-0657 and placebo. Significant antidepressant effects were observed as early as day 5 in patients receiving MK-0657 compared with those receiving placebo, as assessed by the Hamilton Depression Rating Scale and Beck Depression Inventory; however, no improvement was noted when symptoms were assessed with the Montgomery-Asberg Depression Rating Scale, the primary efficacy measure. No serious or dissociative adverse effects were observed in patients receiving this oral formulation of MK-0657. Despite the small sample size, this pilot study suggests that an oral formulation of the NR2B antagonist MK-0657 may have antidepressant properties in TRD patients. Further studies with larger sample sizes are necessary to confirm these preliminary findings.

New female condoms in the pipeline.

Male and female condoms are currently the only effective dual protection methods against unintended pregnancy and transmission of STIs and HIV. In recent years, advocacy and support to female condom (FC) programmes and increased distribution have played a significant role in highlighting to donors, policy-makers and programme managers the importance of FCs as essential tools for dual prevention. Further, the emergence of new FC products, differing in design and materials, has the potential to lower cost and improve acceptability. There are hurdles in developing new FC products, by far the greatest being the clinical studies required for regulatory purposes. However, several new designs are now available in selected countries and some are progressing through the final stages of regulatory approval, after which they will be more widely available. The new FC designs, which may also be more affordable, will increase options and choice for couples who want to use FCs as their prevention method. Here, we review the FC products that are available now and those still in development which are expected to be available within the next two to five years.

Salivary hormonal values from high-speed resistive exercise workouts.

Our study purpose examined salivary hormonal responses to high-speed resistive exercise. Healthy subjects (n = 45) performed 2 elbow flexor workouts on a novel (inertial kinetic exercise; Oconomowoc, WI, USA) strength training device. Our methods included saliva sample collection at both preexercise and immediately postexercise; workouts entailed two 60-second sets separated by a 90-second rest period. The samples were analyzed in duplicate for their testosterone and cortisol concentrations ([T], [C]). Average and maximum elbow flexor torque were measured from each exercise bout; they were later analyzed with a 2(gender) × 2(workout) analysis of variance (ANOVA) with repeated measures for workout. The [T] and [C] each underwent a 2(gender) × 2(time) ANOVA with repeated measures for time. A within-subject design was used to limit error variance. Average and maximum torque each had gender (men > women; p < 0.05) effects. The [T] elicited a 2-way interaction (p < 0.05), as men incurred a significant 14% increase over time, but women's values were unchanged. Yet multivariate regression revealed that 3 predictor variables (body mass and average and maximum torques) did not account for a significant amount of variance associated with the rise in male [T]. Changes in [C] were not significant. In conclusion, changes in [T] concur with the results from other studies that showed significant elevations in male [T], despite the brevity of current workouts and the rather modest volume of muscle mass engaged. Practical applications imply that salivary assays may be a viable alternative to blood draws from athletes, yet coaches and others who may administer this treatment should know that our results may have produced greater pre-post hormonal changes if postexercise sample collection had occurred at a later time point.

Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI.

The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-ß1-42 (Aß(1-42)) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurodegeneration measured by MRI has led to growing interest in using these biomarkers to predict the presence of AD plaque and tangle pathology. A challenge for the widespread use of these CSF biomarkers is the high variability in the assays used to measure these analytes which has been ascribed to multiple pre-analytical and analytical test performance factors. To address this challenge, we conducted a seven-center inter-laboratory standardization study for CSF total tau (t-tau), phospho-tau (p-tau(181)) and Aß(1-42) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Aliquots prepared from five CSF pools assembled from multiple elderly controls (n = 3) and AD patients (n = 2) were the primary test samples analyzed in each of three analytical runs by the participating laboratories using a common batch of research use only immunoassay reagents (INNO-BIA AlzBio3, xMAP technology, from Innogenetics) on the Luminex analytical platform. To account for the combined effects on overall precision of CSF samples (fixed effect), different laboratories and analytical runs (random effects), these data were analyzed by mixed-effects modeling with the following results: within center %CV 95% CI values (mean) of 4.0-6.0% (5.3%) for CSF Aß(1-42); 6.4-6.8% (6.7%) for t-tau and 5.5-18.0% (10.8%) for p-tau(181) and inter-center %CV 95% CI range of 15.9-19.8% (17.9%) for Aß(1-42), 9.6-15.2% (13.1%) for t-tau and 11.3-18.2% (14.6%) for p-tau(181). Long-term experience by the ADNI biomarker core laboratory replicated this degree of within-center precision. Diagnostic threshold CSF concentrations for Aß(1-42) and for the ratio t-tau/Aß(1-42) were determined in an ADNI independent, autopsy-confirmed AD cohort from whom ante-mortem CSF was obtained, and a clinically defined group of cognitively normal controls (NCs) provides statistically significant separation of those who progressed from MCI to AD in the ADNI study. These data suggest that interrogation of ante-mortem CSF in cognitively impaired individuals to determine levels of t-tau, p-tau(181) and Aß(1-42), together with MRI and amyloid imaging biomarkers, could replace autopsy confirmation of AD plaque and tangle pathology as the "gold standard" for the diagnosis of definite AD in the near future.

BIOMARKERS AND NEUROBEHAVIORAL DIAGNOSIS.

Our current diagnostic methods for treatment planning in Psychiatry and Neurodevelopmental Disabilities leave room for improvement, and null results in clinical trials in these fields may be a result of insufficient tools for patient stratification. Great hope has been placed in novel technologies to improve clinical and trial outcomes, but we have yet to see a substantial change in clinical practice. As we examine attempts at biomarker validation within these fields, we find that it may be the diagnoses themselves that fall short. We now need to improve neuropsychiatric nosologies with a focus on validity based not solely on behavioral features, but on a synthesis that includes genetic and biological data as well. The eventual goal is diagnostic biomarkers and diagnoses themselves based on distinct mechanisms, but such an understanding of the causal relationship across levels of analysis is likely to be elusive for some time. Rather, we propose an approach in the near-term that deconstructs diagnosis into a series of independent, empiric and clinically relevant associations among a single, defined patient group, a single biomarker, a single intervention and a single clinical outcome. Incremental study across patient groups, interventions, outcomes and modalities will lead to a more interdigitated network of knowledge, and correlations in metrics across levels of analysis will eventually give way to the causal understanding that will allow for mechanistically based diagnoses.