Psychiatry and the 21st Century: Reworking the DSM.

ABSTRACT: After a long and torturous path, an elusive quest for structure and order may have misled the American Psychiatric Association to overexpand the scope of its Diagnostic and Statistical Manual (DSM) codification of mental disorders. The DSM and guidelines came to represent American psychiatry to the world. Although important for epidemiological and statistical research, in volume and complexity, the DSM challenges clinicians. The DSM effort at categorization must be reconceived to acknowledge modern biological realities. Molecular and other selective biological sciences no longer dominate biology as they did at the time of DSM's initial conception. Today, a Darwinian-Hippocratic combined biology leads psychiatry to address individuals and populations irretrievably and uniquely interdependent with environments. Unfortunately, the DSM, as currently conceived, fails to support this emerging 21st century biological grounding for psychiatry.

Psychiatry's Past Can Be Psychiatry's Future.

In the last half of the 20th century, psychiatry lost many of the conditions needed for unhindered practice. I compiled from searches of the literature the 20th century changes in the arenas of psychiatric practice and the sources of these changes. I determined how these changes are shaping 21st century health and well-being. The neglect of the severely mentally ill, first in Bedlams and now on Boulevards, reflects a wide loss of resources. Psychiatry's patients have lost a past of community-based mental health services, interdisciplinary care teams, preventive consultation with social agencies, and, with reimbursements targeted for 15-minute visits, time adequate with the physician to individualize diagnosis and treatment. With the Covid-19 and other epidemics, economic inequalities, an economic crisis, unrest over police violence, and racism, psychiatry can find in its past the resources to engage 21st century psychiatric and other problems.

(-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer's disease challenged mice.

Mild traumatic brain injury (mTBI) is a risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). TBI-derived neuropathologies are promoted by inflammatory processes: chronic microgliosis and release of pro-inflammatory cytokines that further promote neuronal dysfunction and loss. Herein, we evaluated the effect on pre-programmed cell death/neuroinflammation/synaptic integrity and function of (-)-Phenserine tartrate (Phen), an agent originally developed for AD. This was studied at two clinically translatable doses (2.5 and 5.0 mg/kg, BID), in a weight drop (concussive) mTBI model in wild type (WT) and AD APP/PSEN1 transgenic mice. Phen mitigated mTBI-induced cognitive impairment, assessed by Novel Object Recognition and Y-maze behavioral paradigms, in WT mice. Phen fully abated mTBI-induced neurodegeneration, evaluated by counting Fluoro-Jade C-positive (FJC+) cells, in hippocampus and cortex of WT mice. In APP/PSEN1 mice, degenerating cell counts were consistently greater across all experimental groups vs. WT mice. mTBI elevated FJC+ cell counts vs. the APP/PSEN1 control (sham) group, and Phen similarly mitigated this. Anti-inflammatory effects on microglial activation (IBA1-immunoreactivity (IR)) and the pro-inflammatory cytokine TNF-α were evaluated. mTBI increased IBA1-IR and TNF-α/IBA1 colocalization vs. sham, both in WT and APP/PSEN1 mice. Phen decreased IBA1-IR throughout hippocampi and cortices of WT mice, and in cortices of AD mice. Phen, likewise, reduced levels of IBA1/TNF-α-IR colocalization volume across all areas in WT animals, with a similar trend in APP/PSEN1 mice. Actions on astrocyte activation by mTBI were followed by evaluating GFAP, and were similarly mitigated by Phen. Synaptic density was evaluated by quantifying PSD-95+ dendritic spines and Synaptophysin (Syn)-IR. Both were significantly reduced in mTBI vs. sham in both WT and APP/PSEN1 mice. Phen fully reversed the PSD-95+ spine loss in WT and Syn-IR decrease in both WT and APP/PSEN1 mice. To associate immunohistochemical changes in synaptic markers with function, hippocampal long term potentiation (LTP) was induced in WT mice. LTP was impaired by mTBI, and this impairment was mitigated by Phen. In synopsis, clinically translatable doses of Phen ameliorated mTBI-mediated pre-programmed cell death/neuroinflammation/synaptic dysfunction in WT mice, consistent with fully mitigating mTBI-induced cognitive impairments. Phen additionally demonstrated positive actions in the more pathologic brain microenvironment of AD mice, further supporting consideration of its repurposing as a treatment for mTBI.

Does traumatic brain injury hold the key to the Alzheimer's disease puzzle?

INTRODUCTION: Neurodegenerative disorders have been a graveyard for hundreds of well-intentioned efforts at drug discovery and development. Concussion and other traumatic brain injuries (TBIs) and Alzheimer's disease (AD) share many overlapping pathologies and possible clinical links. METHODS: We searched the literature since 1995 using MEDLINE and Google Scholar for the terms concussion, AD, and shared neuropathologies. We also studied a TBI animal model as a supplement to transgenic (Tg) mouse AD models for evaluating AD drug efficacy by preventing neuronal losses. To evaluate TBI/AD pathologies and neuronal self-induced cell death (apoptosis), we are studying brain extracellular vesicles in plasma and (-)-phenserine pharmacology to probe, in animal models of AD and humans, apoptosis and pathways common to concussion and AD. RESULTS: Neuronal cell death and a diverse and significant pathological cascade follow TBIs. Many of the developing pathologies are present in early AD. The use of an animal model of concussion as a supplement to Tg mice provides an indication of an AD drug candidate's potential for preventing apoptosis and resulting progression toward dementia in AD. This weight drop supplementation to Tg mouse models, the experimental drug (-)-phenserine, and plasma-derived extracellular vesicles enriched for neuronal origin to follow biomarkers of neurodegenerative processes, each and in combination, show promise as tools useful for probing the progression of disease in AD, TBI/AD pathologies, apoptosis, and drug effects on rates of apoptosis both preclinically and in humans. (-)-Phenserine both countered many subacute post-TBI pathologies that could initiate clinical AD and, in the concussion and other animal models, showed evidence consistent with direct inhibition of neuronal preprogrammed cell death in the presence of TBI/AD pathologies. DISCUSSION: These findings may provide support for expanding preclinical Tg mouse studies in AD with a TBI weight drop model, insights into the progression of pathological targets, their relations to apoptosis, and timing of interventions against these targets and apoptosis. Such studies may demonstrate the potential for drugs to effectively and safely inhibit preprogrammed cell death as a new drug development strategy for use in the fight to defeat AD.

Repositioning drugs for traumatic brain injury - N-acetyl cysteine and Phenserine.

Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults of less than 45 years of age and the elderly, and contributes to about 30% of all injury deaths in the United States of America. Whereas there has been a significant improvement in our understanding of the mechanism that underpin the primary and secondary stages of damage associated with a TBI incident, to date however, this knowledge has not translated into the development of effective new pharmacological TBI treatment strategies. Prior experimental and clinical studies of drugs working via a single mechanism only may have failed to address the full range of pathologies that lead to the neuronal loss and cognitive impairment evident in TBI and other disorders. The present review focuses on two drugs with the potential to benefit multiple pathways considered important in TBI. Notably, both agents have already been developed into human studies for other conditions, and thus have the potential to be rapidly repositioned as TBI therapies. The first is N-acetyl cysteine (NAC) that is currently used in over the counter medications for its anti-inflammatory properties. The second is (-)-phenserine ((-)-Phen) that was originally developed as an experimental Alzheimer's disease (AD) drug. We briefly review background information about TBI and subsequently review literature suggesting that NAC and (-)-Phen may be useful therapeutic approaches for TBI, for which there are no currently approved drugs.

Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury.

Traumatic brain injury (TBI), either as an isolated injury or in conjunction with other injuries, is an increasingly common event. An estimated 1.7 million injuries occur within the USA each year and 10 million people are affected annually worldwide. Indeed, nearly one third (30.5%) of all injury-related deaths in the USA are associated with TBI, which will soon outpace many common diseases as the major cause of death and disability. Associated with a high morbidity and mortality and no specific therapeutic treatment, TBI has become a pressing public health and medical problem. The highest incidence of TBI occurs in young adults (15-24 years age) and in the elderly (≥75 years of age). Older individuals are particularly vulnerable to these types of injury, often associated with falls, and have shown increased mortality and worse functional outcome after lower initial injury severity. In addition, a new and growing form of TBI, blast injury, associated with the detonation of improvised explosive devices in the war theaters of Iraq and Afghanistan, are inflicting a wave of unique casualties of immediate impact to both military personnel and civilians, for which long-term consequences remain unknown and may potentially be catastrophic. The neuropathology underpinning head injury is becoming increasingly better understood. Depending on severity, TBI induces immediate neuropathologic effects that, for the mildest form, may be transient; however, with increasing severity, these injuries cause cumulative neural damage and degeneration. Even with mild TBI, which represents the majority of cases, a broad spectrum of neurologic deficits, including cognitive impairments, can manifest that may significantly influence quality of life. Further, TBI can act as a conduit to longer term neurodegenerative disorders. Prior studies of glucagon-like peptide-1 (GLP-1) and long-acting GLP-1 receptor agonists have demonstrated neurotrophic/neuroprotective activities across a broad spectrum of cellular and animal models of chronic neurodegenerative (Alzheimer's and Parkinson's diseases) and acute cerebrovascular (stroke) disorders. In view of the mechanisms underpinning these disorders as well as TBI, we review the literature and recent studies assessing GLP-1 receptor agonists as a potential treatment strategy for mild to moderate TBI.

Fire in the ashes: can failed Alzheimer's disease drugs succeed with second chances?

BACKGROUND: Since Cognex, more than 200 Alzheimer's disease (AD) drug candidates have failed. Investigations have identified vulnerabilities of these AD drug developments to methodological errors. (-)-Phenserine has been discussed as possibly failing due to flawed methods and practices in development. METHODS: We analyzed documentation of (-)-phenserine's development for vulnerabilities to errors and designed interventions for a redevelopment that could provide fair or unbiased assessments of (-)-phenserine target engagement, target relevance for human diseases, and adequate presumptive evidence of efficacy as a therapeutic for one or more diagnoses to justify registration-required clinical trials. RESULTS: Similar to studies of 40 other AD developments, with (-)-phenserine, we found little evidence of preemptive interventions against potentially invalidating errors, grounds to judge progress in development through stages as not scientifically justifiable, and variance excess and placebo group improvements as capable of accounting for outcomes from various studies in the development. We propose to compare a redevelopment resourced to counter these deficiencies with the original development as historical control to evaluate further our hypothesis that errors in development accounted for the (-)-phenserine failure, specifically, and other AD drug failures, potentially. CONCLUSIONS: We find support for our earlier proposal that (-)-phenserine did not fail, but the methods of development did fail, to provide conditions where efficacy could be tested. We propose that redevelopment under conditions aimed to correct methodological deficiencies common in AD drug developments will successfully test efficacy for (-)-phenserine and hopefully lead to a disease-modifying addition to the AD therapeutic armamentarium.

Two Cultures in Modern Science and Technology: For Safety and Validity Does Medicine Have to Update?

Two different scientific cultures go unreconciled in modern medicine. Each culture accepts that scientific knowledge and technologies are vulnerable to and easily invalidated by methods and conditions of acquisition, interpretation, and application. How these vulnerabilities are addressed separates the 2 cultures and potentially explains medicine's difficulties eradicating errors. A traditional culture, dominant in medicine, leaves error control in the hands of individual and group investigators and practitioners. A competing modern scientific culture accepts errors as inevitable, pernicious, and pervasive sources of adverse events throughout medical research and patient care too malignant for individuals or groups to control. Error risks to the validity of scientific knowledge and safety in patient care require systemwide programming able to support a culture in medicine grounded in tested, continually updated, widely promulgated, and uniformly implemented standards of practice for research and patient care. Experiences from successes in other sciences and industries strongly support the need for leadership from the Institute of Medicine's recommended Center for Patient Safely within the Federal Executive branch of government.

(-)-Phenserine tartrate (PhenT) as a treatment for traumatic brain injury.

AIM: Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury-associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI-linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism-targeted drug unlikely. DISCUSSION: We review recent data indicating that the small molecular weight drug (-)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI- and modTBI-induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury-induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well-characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman. CONCLUSION: In the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast-tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.

Neuropsychiatric clinical trials: should they accommodate real-world practices or set standards for clinical practices?

Evidence-based psychiatry seeks the best research evidence for use in patient care. Recent research suggests that problems with accuracy, precision, bias, and other sources of unreliability potentially interfere with the validity of psychiatry's evidence base. Because many negative clinical research studies go unpublished, awareness and fuller understanding of these problems are blocked by lack of access to relevant data. Based on the importance of scientific soundness of neuropsychiatric research and patient care, we argue for increased attentiveness by investigators and practitioners to how clinical trials (CTs) interdependently estimate the efficacy of treatments and the effectiveness of methods as fair tests of efficacy. Deference by CT investigators to real-world practice conditions at research sites because of the unreliability introduced into data by these practices does not ensure unbiased evaluations of treatment efficacy. We argue for more systematic attention to sources of unreliability in CT investigations and increased commitments to assure the validity of the neuropsychiatric evidence base. These recommendations aim to determine neuropsychiatric drug efficacy with greater certainty to better quantify the clinical importance of drug-associated effects and to provide CT-evidenced guidance for practitioners to most effectively use drug efficacy in patient care.

Can We Prevent Dementia and Not Prevent Neurons from Dying?

Neuronal death is the final step in the progression of preclinical Alzheimer's disease (AD) pathologies into clinically evident AD and its profound dementia. As such, a drug candidate proposed to be effective in AD must successfully prevent neuronal losses. The lack of preclinical demonstrated abilities to prevent neuronal programmed cell death may explain the recent failure of 300-400 AD drug candidates, identify a flaw in the Amyloid Hypothesis, and a risk for subsequent drug candidate interventions against AD. We propose that investigators use either animal models or small early translational clinical trials to test for AD drug candidates' efficacy against clinically critical features of the disease, such as prevention of neuronal death. Such stringent testing would more effectively shelter AD patients from being recruited into clinical trials that are destined to fail in Phase II or III.

Geriatric pharmacotherapy: Appraising new drugs for neurologic disorders in older patients.

New drug development for neurologic disorders has one of the highest attrition rates of all clinical drug developments. This is problematic when, with innovative technology available in so many aspects of life, modern societies expect to have effective treatments for neurodegenerative disorders and mental health conditions that provide something beyond simple symptomatic relief-the expectation is treatment that impacts and mitigates fundamental mechanisms that drive these disorders. The disease burden of neurologic disorders remains extremely high, whereas the proportion of patients receiving effective therapy is relatively low, demonstrating a sizeable unmet medical need. Whether for novel breakthrough therapies or for drugs considered successful, deciding on the basis of clinical trial data whether a particular treatment will be effective for a specific patient is always a leap of faith. However, expertise at reading trial results combined with knowledge of the patient and of his or her disease, together with an understanding of the effect of age on drug pharmacokinetics and pharmacodynamics, the effect of age on the patient's condition, and the effect of age on the patient's life and outlook will ensure the landing is safe. The focus of this article is to provide such knowledge and thereby optimize this expertise.

Neuronal Enriched Extracellular Vesicle Proteins as Biomarkers for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of injury-related death throughout the world and lacks effective treatment. Surviving TBI patients often develop neuropsychiatric symptoms, and the molecular mechanisms underlying the neuronal damage and recovery following TBI are not well understood. Extracellular vesicles (EVs) are membranous nanoparticles that are divided into exosomes (originating in the endosomal/multi-vesicular body [MVB] system) and microvesicles (larger EVs produced through budding of the plasma membrane). Both types of EVs are generated by all cells and are secreted into the extracellular environment, and participate in cell-to-cell communication and protein and RNA delivery. EVs enriched for neuronal origin can be harvested from peripheral blood samples and their contents quantitatively examined as a window to follow potential changes occurring in brain. Recent studies suggest that the levels of exosomal proteins and microRNAs (miRNAs) may represent novel biomarkers to support the clinical diagnosis and potential response to treatment for neurological disorders. In this review, we focus on the biogenesis of EVs, their molecular composition, and recent advances in research of their contents as potential diagnostic tools for TBI.

Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices?

Alzheimer's disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, and lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice.

Alzheimer's disease drug development in 2008 and beyond: problems and opportunities.

Recently, a number of Alzheimer's disease (AD) multi-center clinical trials (CT) have failed to provide statistically significant evidence of drug efficacy. To test for possible design or execution flaws we analyzed in detail CTs for two failed drugs that were strongly supported by preclinical evidence and by proven CT AD efficacy for other drugs in their class. Studies of the failed commercial trials suggest that methodological flaws may contribute to the failures and that these flaws lurk within current drug development practices ready to impact other AD drug development [1]. To identify and counter risks we considered the relevance to AD drug development of the following factors: (1) effective dosing of the drug product, (2) reliable evaluations of research subjects, (3) effective implementation of quality controls over data at research sites, (4) resources for practitioners to effectively use CT results in patient care, (5) effective disease modeling, (6) effective research designs. New drugs currently under development for AD address a variety of specific mechanistic targets. Mechanistic targets provide AD drug development opportunities to escape from many of the factors that currently undermine AD clinical pharmacology, especially the problems of inaccuracy and imprecision associated with using rated outcomes. In this paper we conclude that many of the current problems encountered in AD drug development can be avoided by changing practices. Current problems with human errors in clinical trials make it difficult to differentiate drugs that fail to evidence efficacy from apparent failures due to Type II errors. This uncertainty and the lack of publication of negative data impede researchers' abilities to improve methodologies in clinical pharmacology and to develop a sound body of knowledge about drug actions. We consider the identification of molecular targets as offering further opportunities for overcoming current failures in drug development.

Patients Are Our Teachers.

In the patient-physician encounter, physicians hone their skills while alleviating the patient's suffering. Both benefit. Leaning on the work of Hippocrates, Darwin, and William Osler, the authors sketch out the case for honoring patients as indispensable teachers of the art and science of medicine. They argue that this tradition of Hippocratic medicine both anticipates modern precision medicine and reawakens a focus on public health medicine, each a benefit to the patients and communities served by physicians. A community that compromises the learning relationship of physician to patient and population undermines quality of care.

(-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer's Disease.

BACKGROUND: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate's potential for preventing PPCD and resulting progression towards dementia in AD. METHODS: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods. RESULTS: We identified and address seven issues and highlight the Thal-Sano AD 'Time to Onset of Impairment' Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs. CONCLUSIONS: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.