Therapeutics In Psychiatry Research Articles

Biological subtyping of psychiatric syndromes as a pathway for advances in drug discovery and personalized medicine

Every common psychiatric syndrome is genetically, neurobiologically and clinically heterogeneous. This heterogeneity may reflect the dimensional variability of a single illness with common etiology, varying in severity. Alternatively, as in many areas of medicine, it may reflect different discrete types of illness leading to similar alterations of mood or behavior. Resolving uncertainty as to the nature of heterogeneity in psychiatric illness is crucial for advancing the development of novel therapeutics and improving the precision with which pharmacological interventions are chosen for specific patients. Recent work resolving illness heterogeneity has shown promise in identifying biologically distinct patient subgroups within common psychiatric syndromes. This progress offers hope for the longer-term aim of enhancing our understanding of biological alterations associated with psychiatric syndromes, so that drug development and pharmacological interventions can shift towards altering specific targeted biological processes, instead of working to change complex behavioral features that may represent the final common pathway of different biological illness mechanisms. Using approaches such as neuroimaging and peripheral immune markers, studies have identified subgroups with different patterns of biological features that provide translational targets for novel drug development programmes, and may, in the longer term, together with psychological and social perspectives, more closely link diagnostics and therapeutics in psychiatry. So far, multiple discrete subgroups have been identified, and these have been associated with clinical features. Work is now needed to improve the validity and reliability of biologically derived subtypes, and better characterize their clinical, developmental and psychosocial features. This is required to establish their clinical utility for predicting illness course and response to different therapies, and to determine how biologically distinct features of patient subgroups can guide the development of novel therapies targeting those alterations.

Burning down the house: reinventing drug discovery in psychiatry for the development of targeted therapies.

Despite advances in neuroscience, limited progress has been made in developing new and better medications for psychiatric disorders. Available treatments in psychiatry rely on a few classes of drugs that have a broad spectrum of activity across disorders with limited understanding of mechanism of action. While the added value of more targeted therapies is apparent, a dearth of pathophysiologic mechanisms exists to support targeted treatments, and where mechanisms have been identified and drugs developed, results have been disappointing. Based on serendipity and early successes that led to the current drug armamentarium, a haunting legacy endures that new drugs should align with outdated and overinclusive diagnostic categories, consistent with the idea that "one size fits all". This legacy has fostered clinical trial designs focused on heterogenous populations of patients with a single diagnosis and non-specific outcome variables. Disturbingly, this approach likely contributed to missed opportunities for drugs targeting the hypothalamic-pituitary-adrenal axis and now inflammation. Indeed, cause-and-effect data support the role of inflammatory processes in neurotransmitter alterations that disrupt specific neurocircuits and related behaviors. This pathway to pathology occurs across disorders and warrants clinical trial designs that enrich for patients with increased inflammation and use primary outcome variables associated with specific effects of inflammation on brain and behavior. Nevertheless, such trial designs have not been routinely employed, and results of anti-inflammatory treatments have been underwhelming. Thus, to accelerate development of targeted therapeutics including in the area of inflammation, regulatory agencies and the pharmaceutical industry must embrace treatments and trials focused on pathophysiologic pathways that impact specific symptom domains in subsets of patients, agnostic to diagnosis. Moreover, closer collaboration among basic and clinical investigators is needed to apply neuroscience knowledge to reveal disease mechanisms that drive psychiatric symptoms. Together, these efforts will support targeted treatments, ultimately leading to new and better therapeutics in psychiatry.

Linking Individual Differences in Personalized Functional Network Topography to Psychopathology in Youth

BackgroundThe spatial layout of large-scale functional brain networks differs between individuals and is particularly variable in the association cortex, implicated in a broad range of psychiatric disorders. However, it remains unknown whether this variation in functional topography is related to major dimensions of psychopathology in youth. MethodsThe authors studied 790 youths ages 8 to 23 years who had 27 minutes of high-quality functional magnetic resonance imaging data as part of the Philadelphia Neurodevelopmental Cohort. Four correlated dimensions were estimated using a confirmatory correlated traits factor analysis on 112 item-level clinical symptoms, and one overall psychopathology factor with 4 orthogonal dimensions were extracted using a confirmatory factor analysis. Spatially regularized nonnegative matrix factorization was used to identify 17 individual-specific functional networks for each participant. Partial least square regression with split-half cross-validation was conducted to evaluate to what extent the topography of personalized functional networks encodes major dimensions of psychopathology. ResultsPersonalized functional network topography significantly predicted unseen individuals’ major dimensions of psychopathology, including fear, psychosis, externalizing, and anxious-misery. Reduced representation of association networks was among the most important features for the prediction of all 4 dimensions. Further analysis revealed that personalized functional network topography predicted overall psychopathology (r = 0.16, permutation testing p < .001), which drove prediction of the 4 correlated dimensions. ConclusionsThese results suggest that individual differences in functional network topography in association networks is related to overall psychopathology in youth. Such results underscore the importance of considering functional neuroanatomy for personalized diagnostics and therapeutics in psychiatry.

Application of evoked response audiometry for specifying aberrant gamma oscillations in schizophrenia

Gamma oscillations probed using auditory steady-state response (ASSR) are promising clinical biomarkers that may give rise to novel therapeutic interventions for schizophrenia. Optimizing clinical settings for these biomarker-driven interventions will require a quick and easy assessment system for gamma oscillations in psychiatry. ASSR has been used in clinical otolaryngology for evoked response audiometry (ERA) in order to judge hearing loss by focusing on the phase-locked response detectability via an automated analysis system. Herein, a standard ERA system with 40- and 46-Hz ASSRs was applied to evaluate the brain pathophysiology of patients with schizophrenia. Both ASSRs in the ERA system showed excellent detectability regarding the phase-locked response in healthy subjects and sharply captured the deficits of the phase-locked response caused by aberrant gamma oscillations in individuals with schizophrenia. These findings demonstrate the capability of the ERA system to specify patients who have aberrant gamma oscillations. The ERA system may have a potential to serve as a real-world clinical medium for upcoming biomarker-driven therapeutics in psychiatry.

Circuit-Targeted Neuromodulation for Anhedonia.

Despite the prevalence of anhedonia across multiple psychiatric disorders, its relevance to treatment selection and prognostication can be unclear (Davey et al., Psychol Med 42(10):2071-81, 2012). Given the challenges in pharmacological and psychosocial treatment, there has been increasing attention devoted to neuroanatomically-targeted treatments. This chapter will present a brief introduction to circuit-targeted therapeutics in psychiatry (Sect. 1), an overview of brain mapping as it relates to anhedonia (Sect. 2), a review of existing studies on brain stimulation for anhedonia (Sect. 3), and a description of emerging approaches to circuit-based neuromodulation for anhedonia (Sect. 4).

Classical Psychedelics as Therapeutics in Psychiatry - Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders.

Classical psychedelics, primarily psilocybin and lysergic acid diethylamide (LSD), have been used and extensively studied in Western medicine as part of substance-assisted psychotherapy in the 1950s and 1960s. Modern clinical research is currently gaining momentum and provides new evidence for the safety and efficacy of classical psychedelics (primarily psilocybin, but also LSD and ayahuasca) in the treatment of different psychiatric conditions, including substance use and mood disorders.In this review article, we outline common pathological mechanisms of substance use disorders (SUD) and unipolar depression. Next, the current literature on the effects of psychedelics is summarized in order to generate hypotheses regarding their potential therapeutic mechanisms of action in treating these psychiatric conditions. Finally, we review and discuss clinical trials published since 2011 investigating the effects of psychedelics in SUD and depression.While results from those modern clinical trials are promising, most of them do not meet the methodological requirements to allow firm conclusions on the clinical efficacy of psychedelics. Larger, blinded, randomized controlled trials (RCT) with clearly defined patient groups and well-defined primary endpoints are needed. Additionally, the therapeutic mechanisms of classical psychedelics are currently unknown. This review presents hypotheses derived from preclinical and human studies that need to be tested in future trials to better understand the clinical potential of psychedelic substances in modern psychiatry.

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms.

Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin-, brain-derived neurotrophic factor-, and early growth response-related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds. SIGNIFICANCE STATEMENT: Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.

Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review

BackgroundMedicinal cannabis has received increased research attention over recent years due to loosening global regulatory changes. Medicinal cannabis has been reported to have potential efficacy in reducing pain, muscle spasticity, chemotherapy-induced nausea and vomiting, and intractable childhood epilepsy. Yet its potential application in the field of psychiatry is lesser known.MethodsThe first clinically-focused systematic review on the emerging medical application of cannabis across all major psychiatric disorders was conducted. Current evidence regarding whole plant formulations and plant-derived cannabinoid isolates in mood, anxiety, sleep, psychotic disorders and attention deficit/hyperactivity disorder (ADHD) is discussed; while also detailing clinical prescription considerations (including pharmacogenomics), occupational and public health elements, and future research recommendations. The systematic review of the literature was conducted during 2019, assessing the data from all case studies and clinical trials involving medicinal cannabis or plant-derived isolates for all major psychiatric disorders (neurological conditions and pain were omitted).ResultsThe present evidence in the emerging field of cannabinoid therapeutics in psychiatry is nascent, and thereby it is currently premature to recommend cannabinoid-based interventions. Isolated positive studies have, however, revealed tentative support for cannabinoids (namely cannabidiol; CBD) for reducing social anxiety; with mixed (mainly positive) evidence for adjunctive use in schizophrenia. Case studies suggest that medicinal cannabis may be beneficial for improving sleep and post-traumatic stress disorder, however evidence is currently weak. Preliminary research findings indicate no benefit for depression from high delta-9 tetrahydrocannabinol (THC) therapeutics, or for CBD in mania. One isolated study indicates some potential efficacy for an oral cannabinoid/terpene combination in ADHD. Clinical prescriptive consideration involves caution in the use of high-THC formulations (avoidance in youth, and in people with anxiety or psychotic disorders), gradual titration, regular assessment, and caution in cardiovascular and respiratory disorders, pregnancy and breast-feeding.ConclusionsThere is currently encouraging, albeit embryonic, evidence for medicinal cannabis in the treatment of a range of psychiatric disorders. Supportive findings are emerging for some key isolates, however, clinicians need to be mindful of a range of prescriptive and occupational safety considerations, especially if initiating higher dose THC formulas.

Électroconvulsivothérapie et niveau de preuve : de la causalité à la relation dose-effet

The first objective of this article is to summarize the history of electroconvulsive therapy (ECT) in psychiatry in order to highlight the transition from clinical level of evidence based on phenomenological descriptions to controlled trial establishing causal relationship. The second objective is to apply the criteria of causation for ECT, to focus on the dose-effect relationship criteria, and thus to analyze the conditions of application of these criteria for ECT. A literature review exploring the use of electricity, ECT and electroencephalography (EEG) in psychiatry was conducted. The publications were identified from the Pubmed and GoogleScholar electronic databases. The scientific literature search of international articles was performed in July 2016. In 1784, a Royal commission established in France by King Louis XVI tested Mesmer's claims concerning animal magnetism. By doing that, the commission, including such prominent scientists as the chemist Anton Lavoisier and the scientist and researcher on electricity and therapeutics Benjamin Franklin, played a central role in establishing the criteria needed to assess the level of evidence of electrical therapeutics in psychiatry. Surprisingly, it is possible to identify the classical Bradford Hill criteria of causation in the report of the commission, except the dose-effect relationship criteria. Since then, it has been conducted blinded randomized controlled trials that confirmed the effectiveness of ECT against ECT placebos for the treatment of psychiatric disorders. At present, the dose-effect relationship criteria can be analyzed through an EEG quality assessment of ECT-induced seizures. EEG quality assessment includes several indices: TSLOW (time to onset of seizure activity ≤5Hz, seconds), peak mid-ictal amplitude (mm), regularity (intensity or morphology of the seizure (0-6)), stereotypy (global seizure patterning, 0-3) and post-ictal suppression (0-3). A manual rating sheet is needed to score theses indices. Such manual rating with example of EEG segments recording is proposed in this article. Additional studies are needed to validate this manual, to better establish the dose-response relationship for the ECT, and thus strengthen the position of the EEG as a central element for clinical good practice for ECT.

The effects of Rpd3 on fly metabolism, health, and longevity

The epigenetic regulation of DNA structure and function is essential for changes in gene expression involved in development, growth, and maintenance of cellular function. Epigenetic changes include histone modifications such as methylation, acetylation, ubiquitination, and phosphorylation. Histone deacetylase (HDAC) proteins have a major role in epigenetic regulation of chromatin structure. HDACs are enzymes that catalyze the removal of acetyl groups from lysine residues within histones, as well as a range of other proteins including transcriptional factors. HDACs are highly conserved proteins divided into two families and based on sequence similarity in four classes. Here we will discuss the roles of Rpd3 in physiology and longevity with emphasis on its role in flies. Rpd3, the Drosophila HDAC1 homolog, is a class I lysine deacetylase and a member of a large family of HDAC proteins. Rpd3 has multiple functions including control of proliferation, development, metabolism, and aging. Pharmacological and dietary HDAC inhibitors have been used as therapeutics in psychiatry, cancer, and neurology.

Personalized medicine beyond genomics: alternative futures in big data-proteomics, environtome and the social proteome.

No field in science and medicine today remains untouched by Big Data, and psychiatry is no exception. Proteomics is a Big Data technology and a next generation biomarker, supporting novel system diagnostics and therapeutics in psychiatry. Proteomics technology is, in fact, much older than genomics and dates to the 1970s, well before the launch of the international Human Genome Project. While the genome has long been framed as the master or "elite" executive molecule in cell biology, the proteome by contrast is humble. Yet the proteome is critical for life-it ensures the daily functioning of cells and whole organisms. In short, proteins are the blue-collar workers of biology, the down-to-earth molecules that we cannot live without. Since 2010, proteomics has found renewed meaning and international attention with the launch of the Human Proteome Project and the growing interest in Big Data technologies such as proteomics. This article presents an interdisciplinary technology foresight analysis and conceptualizes the terms "environtome" and "social proteome". We define "environtome" as the entire complement of elements external to the human host, from microbiome, ambient temperature and weather conditions to government innovation policies, stock market dynamics, human values, political power and social norms that collectively shape the human host spatially and temporally. The "social proteome" is the subset of the environtome that influences the transition of proteomics technology to innovative applications in society. The social proteome encompasses, for example, new reimbursement schemes and business innovation models for proteomics diagnostics that depart from the "once-a-life-time" genotypic tests and the anticipated hype attendant to context and time sensitive proteomics tests. Building on the "nesting principle" for governance of complex systems as discussed by Elinor Ostrom, we propose here a 3-tiered organizational architecture for Big Data science such as proteomics. The proposed nested governance structure is comprised of (a) scientists, (b) ethicists, and (c) scholars in the nascent field of "ethics-of-ethics", and aims to cultivate a robust social proteome for personalized medicine. Ostrom often noted that such nested governance designs offer assurance that political power embedded in innovation processes is distributed evenly and is not concentrated disproportionately in a single overbearing stakeholder or person. We agree with this assessment and conclude by underscoring the synergistic value of social and biological proteomes to realize the full potentials of proteomics science for personalized medicine in psychiatry in the present era of Big Data.

Metagenomics: A New Frontier for Translational Research and Personalized Therapeutics in Psychiatry?

Metagenomics: A New Frontier for Translational Research and Personalized Therapeutics in Psychiatry?

The role of dietary histone deacetylases (HDACs) inhibitors in health and disease.

Modification of the histone proteins associated with DNA is an important process in the epigenetic regulation of DNA structure and function. There are several known modifications to histones, including methylation, acetylation, and phosphorylation, and a range of factors influence each of these. Histone deacetylases (HDACs) remove the acetyl group from lysine residues within a range of proteins, including transcription factors and histones. Whilst this means that their influence on cellular processes is more complex and far-reaching than histone modifications alone, their predominant function appears to relate to histones; through deacetylation of lysine residues they can influence expression of genes encoded by DNA linked to the histone molecule. HDAC inhibitors in turn regulate the activity of HDACs, and have been widely used as therapeutics in psychiatry and neurology, in which a number of adverse outcomes are associated with aberrant HDAC function. More recently, dietary HDAC inhibitors have been shown to have a regulatory effect similar to that of pharmacological HDAC inhibitors without the possible side-effects. Here, we discuss a number of dietary HDAC inhibitors, and how they may have therapeutic potential in the context of a whole food.

Personalized Medicine, Pharmacogenomics, and the Practice of Psychiatry: On the Threshold of Predictive Therapeutics in Psychopharmacology?

Personalizing medicine by understanding the unique properties of each patient's genome has the potential of predicting what drug to prescribe for that individual. This approach has already proven useful for several drugs in medicine and promises to become a strategy for selection of therapeutics in psychiatry soon. Understanding some of the key concepts, strategies, and advances in the field of pharmacogenomics can set the stage for adapting emerging findings to the practice of psychopharmacology.

Neuropsychopharmacology: The Fifth Generation of Progress

Back to table of contents Previous article Next article Book Forum: PsychopharmacologyFull AccessNeuropsychopharmacology: The Fifth Generation of ProgressKEMAL SAGDUYU, M.D., KEMAL SAGDUYUSearch for more papers by this author, M.D., Kansas City, Mo.Published Online:1 Jul 2002https://doi.org/10.1176/appi.ajp.159.7.1251-aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Drs. Davis, Charney, Coyle, and Nemeroff have sculpted the fifth masterpiece of Neuropsychopharmacology. Following the new tradition set by its immediate predecessor, this edition provides an even more comprehensive overview of the preclinical and clinical arms of the field. The book not only provides basic and clinical scientists with overviews of preclinical and clinical psychopharmacology but also devotes more detailed coverage to help the reader understand the methods by which data in each of these arms are assessed in research. The introductory sections provide a basis for the detailed coverage of the enormous amount of progress that has been achieved since the previous volume.Skillfully revised, updated, and restructured, Neuropsychopharmacology: The Fifth Generation of Progress incorporates the latest basic and clinical advances in neuropsychopharmacology and identifies promising new areas of investigation. In the tradition of its acclaimed predecessors, this volume establishes a critical bridge connecting the principles of molecular and cellular biology with the etiology, diagnosis, treatment, and prevention of neuropsychiatric disorders and substance abuse. More than any other work in the field, this book consistently and successfully integrates basic neurobiology, biological psychiatry, and clinical psychopharmacology.The first four sections of the book cover preclinical and clinical psychopharmacology. The preclinical section features an extensive review and update of all currently known neurotransmitter systems and signal transduction. The following sections focus on molecular biology and genetics, with an especially appealing chapter titled “Applying Functional Genomics to Neuropsychopharmacology.” Section 3, Emerging Imaging Technologies and Their Application to Psychiatric Research, makes it easier for educators and clinicians to help medical students understand and accept the fact that the brain is the final frontier and psychiatry is the best field of medicine to practice in this century. Section 4, Drug Discovery and Evaluation, includes two very valuable chapters, “The Role of Pharmaceuticals in Mental Health Care Outcomes” and “Issues in Clinical Designs.”The following nine clinical sections provide a comprehensive update on the etiology, biology, and treatment of the entire spectrum of psychiatric and neuropsychiatric disorders. Each section also includes critical analyses of current research methods and key integrative concepts. New chapters worth special attention include “Gene Delivery Into the Brain Using Viral Vectors,” “Diffusion Tensor Imaging,” and “Pharmacogenomics and Personalized Therapeutics in Psychiatry.”This book has come a long way since the admirable Psychopharmacology: The Third Generation of Progress(1). The new edition is a must for the library of every medical school, basic medical science, and psychiatric hospital library as well for all those who are in the basic and clinical fields close to neuropsychopharmacology.A bonus to obtaining this book is that it gives the purchaser the option to gain free online access to Neuropsychopharmacology, the official journal of the American College of Neuropsychopharmacology. A must-do for everybody who purchases the book!Edited by Kenneth L. Davis, M.D., Dennis Charney, M.D., Joseph T. Coyle, M.D., and Charles Nemeroff, M.D., Ph.D. Philadelphia, Lippincott Williams & Wilkins, 2002, 2,010 pp., $189.00.Reference1. Meltzer HY (ed): Psychopharmacology: The Third Generation of Progress. New York, Raven Press, 1987Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 159Issue 7 July 2002Pages 1251-a-1252 Metrics PDF download History Published online 1 July 2002 Published in print 1 July 2002

A public health approach to clinical therapeutics in psychiatry: directions for new research

The mental health field is transforming the culture of treatment research by moving from a narrow regulatory model geared to drug approval and registration to a more inclusive public health model. Thus, whereas regulatory antidementia trials will exclude patients with psychiatric or neurologic symptoms or substance abuse and require them to be physically healthy and living with a caregiver, ie, 90% of the presenting Alzheimer population, the public health model promises to improve patient care by addressing the types of practical questions and functional outcomes typically the concern of clinicians: Does treatment enhance function? How can we keep people well once they have been made well? Why do treatments not work as well in practice as in clinical trials? Public health studies are conducted in the world of actual practice with time-pressured clinicians taking care of large numbers of patients with uncertain clinical presentations, complex comorbidities, and varying degrees of interference with ideal levels of compliance. The exclusive focus on symptoms is expanded to include outcomes related to issues of function, disability, morbidity, mortality, resource use, and quality of life. Highly controlled efficacy research is still needed to establish treatment merit, but efficacy now marks only the beginning of the process of inquiry.

Evil or Ill? Justifying the Insanity Defense

Evil or Ill? Justifying the Insanity Defense

Book Review: Differential Therapeutics in Psychiatry: The Art and Science of Treatment Selection

Book Review: Differential Therapeutics in Psychiatry: The Art and Science of Treatment Selection

Differential Therapeutics in Psychiatry: The Art and Science of Treatment Selection

Differential Therapeutics in Psychiatry: The Art and Science of Treatment Selection

Differential Therapeutics in Psychiatry: The Art and Science of Treatment Selection

Differential Therapeutics in Psychiatry: The Art and Science of Treatment Selection