Development Of Psychotropic Drugs Research Articles

Psychedelic and dissociative agents in psychiatry: challenges in the treatment

With the discovery of the antidepressive effects of ketamine and the increasing withdrawal of the pharmaceutical industry from the development of new psychotropic drugs, the psychiatric research into the clinical application of hallucinogens in psychiatry has literally blossomed in the last two decades. Promising results for various treatment approaches with psychedelic agents, such lysergic acid diethylamide (LSD) and psilocybin, and dissociative agents, such as ketamine and esketamine, have raised great hopes among researchers, clinicians and patients in recent years, so that there was already talk of a new era in psychiatry. As one of the first of these substances, in December 2019 intranasal esketamine was approved in the USA and the EU for the treatment of treatment-resistant depression and Switzerland followed in 2020. Recently, psilocybin was approved in Australia, Canada and Switzerland for compassionate use in exceptional cases for the treatment of depression, while large approval studies with various psychedelic agents are currently ongoing worldwide. The medical application of psychedelic agents and ketamine/esketamine is considered to be safe; however, as with all new forms of treatment it is of crucial importance that, in addition to the hopes, the specific challenges of these new treatment approaches must also be carefully considered and assessed. Excessive expectations and an insufficient risk-benefit estimation are detrimental to the patients and the reputation of the treating physician. Although a possible paradigm shift in the care of mental health is already being discussed, this review article consciously concentrates on the possible risks of treatment and the methodological weaknesses of the studies carried out so far.

The future of psychopharmacology: challenges beyond efficacy and tolerability.

The future of psychopharmacology: challenges beyond efficacy and tolerability.

Development of Novel Psychotropic Drugs by an Alcohol Abstinence Drug Disulfiram

Development of Novel Psychotropic Drugs by an Alcohol Abstinence Drug Disulfiram

An emotional stress model using witnessing social defeat scenes in mice

Chronic exposure to stress can lead to a variety of mental disorders such as depression. There are many treatment-resistant patients who do not respond adequately to the standard pharmacological treatments. Therefore, the development of novel therapeutic agents is highly expected. In rodents, socially defeated animals that were exposed to repeated physical aggression from other individuals are widely used in this field of research. The social defeat is considered as a stress that mimics human social stress. On the other hand, emotional stress, but not physical stress, is likely to contribute to the pathogenesis and etiology of depression in human. Therefore, there is a gap between the process of pathogenesis and the animal models, and this is one of the reasons why the development of new psychotropic drugs to treat depression has been difficult. Recently, a novel stress model has been introduced, in which mice are subjected to emotional stress without physical distress by witnessing social defeat scenes of their conspecifics. We have investigated the mechanisms by which emotional stress is transmitted by witnessing social defeat in mice, focusing on the insular cortex. In this article, we summarize and discuss the recent advancements in the neural basis of behavioral changes induced by emotional stress.

J Guy Edwards, FRCPsych, FRCP, FRCGP (Hon), DPM, HonMFPH, Founding Editor of Human Psychopharmacology.

J Guy Edwards, FRCPsych, FRCP, FRCGP (Hon), DPM, HonMFPH, Founding Editor of Human Psychopharmacology.

Potential of delta opioid receptor agonists for the development of novel psychotropic drugs

Potential of delta opioid receptor agonists for the development of novel psychotropic drugs

Melatonin Regulates the Neurotransmitter Secretion Disorder Induced by Caffeine Through the Microbiota-Gut-Brain Axis in Zebrafish (Danio rerio).

Melatonin has been widely used as a “probiotic agent” capable of producing strong neurotransmitter secretion regulatory effects, and the microbiota-gut-brain axis-related studies have also highlighted the role of the gut microbiota in neuromodulation. In the present study, a zebrafish neural hyperactivity model was established using caffeine induction to explore the regulatory effects of melatonin and probiotic on neurotransmitter secretion disorder in zebrafish. Disorders of brain neurotransmitter secretion (dopamine, γ-aminobutyric acid, and 5-hydroxytryptamine) caused by caffeine were improved after interference treatment with melatonin or probiotic. Shotgun metagenomic sequencing demonstrated that the melatonin-treated zebrafish gradually restored their normal intestinal microbiota and metabolic pathways. Germ-free (GF) zebrafish were used to verify the essential role of intestinal microbes in the regulation of neurotransmitter secretion. The results of the neurotransmitter and short-chain fatty acid determination revealed that the effect on the zebrafish in the GF group could not achieve that on the zebrafish in the melatonin group after adding the same dose of melatonin. The present research revealed the potential mode of action of melatonin through the microbiota-gut-brain axis to regulate the disruption of neurotransmitter secretion, supporting the future development of psychotropic drugs targeting the intestinal microbiota.

Hallucinations: diagnosis, neurobiology and clinical management

Hallucinations are important diagnostic symptoms in schizophrenia, but also occur in other medical and neuropsychiatric conditions. Not all patients with hallucinations are psychotic. There has been a surge of interest in the topic of hallucinations, as new research data have begun to reveal their neurobiology. Hallucinogenic molecules may also serve as new scaffolds for the development of new psychotropic drugs. We searched and reviewed recent literature, focusing on the refinement of clinical management, which was inspired by new data regarding the neurobiology of hallucination subtypes. We concluded that the successful management of hallucinations depends on accurate differential diagnosis to identify subtypes, which would then determine the most appropriate treatment.

Do DSM classifications help or hinder drug development? .

Development and regulatory approval of psychotropic drugs targets individuals with syndromes described in the current Diagnostic and Statistical Manual of Mental Disorders (DSM). This helps drug developers and regulators to communicate with prescribers, and prescribers to match a specific psychotropic with the individual patient(s) most likely to benefit from it. However, this practice has been criticized on the grounds that DSM syndromes are too heterogenous biologically, and the effects of psychotropics are too nonspecific to allow for an effective match. This review considers the advantages and disadvantages of the current practice and the possible alternatives. It concludes that efforts should be made to explore psychotropic development transdiagnostically, free of the DSM boundaries. However, currently there exists no alternative diagnostic system that is clearly superior to the DSM in terms of communications between the stakeholders in drug development.

Research and development of κ opioid receptor agonists and δ opioid receptor agonists.

Delta opioid delta receptor (DOP) agonists were expected to be analgesics and many researchers tried to develop the SNC80 derivatives. However, the derivatives were dropped at the stage of early clinical trials because of undesirable side effects and weak analgesia. On the other hand, DOP agonists have been proposed as attractive candidates for the novel psychotropic drugs. We recently succeeded in synthesizing a novel selective DOP agonist KNT-127. KNT-127 produced neither catalepsy nor convulsive effects. We have demonstrated that KNT-127 has potent anxiolytic-like effect in rat models of innate anxiety. This anxiolytic-like effect was independent from known adverse effect of benzodiazepine, such as memory impairment, motor coordination deficits, and ethanol interactions. We have also demonstrated that KNT-127 showed potent and rapid antidepressant-like effects in rat models of depression. This antidepressant-like effect was independent from known adverse effect of selective serotonin reuptake inhibitor (SSRI), such as digestive symptoms. Therefore, we propose that DOP should be considered as an attractive target for the development of novel psychotropic drugs, without producing the adverse effects associated with benzodiazepine anxiolytics and SSRI antidepressants. Very recently, we developed another delta agonist NC-2800 with a different structure. NC-2800 is now in the preclinical stage using the CiCLE fund supported by AMED (Japanese Agency for Medical Research and Development).

Opportunities in Novel Psychotropic Drug Design from Natural Compounds.

Multiple initiatives at the national and international level support natural drug discovery. Psychiatrists and patients are not well informed about natural psychotropics in general. Existing antidepressant and antipsychotic drugs were developed from atropine, a natural product. Subsequent drug developments were largely based on extension and modification of earlier molecular scaffolds. This limits their mechanisms of action to similar neuropathways. Natural psychotropic substances, particularly those with hallucinogenic and psychedelic properties and different chemical structures, may serve as new paths to novel psychotropic drug development.

A Selective Summary of Psychopharmacology Research Published in Second Half of 2017

Psychotropic drug development has largely stalled in recent times. Many novel ideas have appeared, but practical choices available to psychiatrists remain mostly unchanged. Two new medications are building up momentum to enter regular clinical use (Articles 1 & 2). Many of us have wished for an effective depot antipsychotic injection that lasts for a few months, and new longer acting formulations are now entering the market (Article 3). Predicting non-responders earlier during the course of treatment is always a clinical priority, and there are two interesting new studies in this regard (Articles 6 & 9). Optimum dosing of antidepressants and antipsychotics is often controversial, but its importance cannot be overlooked (Article 4 & 5). Clozapine is once again drawing attention with its better comparative efficacy, this time demonstrating it in routine clinical practice (Article 7). We have a more reliable variable to look for while monitoring clinical improvement in patients on antidepressants (Article 8). New research raises questions about the efficacy of interventions for negative symptoms (Article 9) and that of anti-inflammatory therapies for psychiatric disorders (Article 10). 1. ANY NEW MEDICATIONS EMERGING FOR BIPOLAR DEPRESSION?

A Selective Summary of Psychopharmacology Research Published in Second Half of 2017

Psychotropic drug development has largely stalled in recent times. Many novel ideas have appeared, but practical choices available to psychiatrists remain mostly unchanged. Two new medications are building up momentum to enter regular clinical use (Articles 1 & 2). Many of us have wished for an effective depot antipsychotic injection that lasts for a few months, and new longer acting formulations are now entering the market (Article 3). Predicting non-responders earlier during the course of treatment is always a clinical priority, and there are two interesting new studies in this regard (Articles 6 & 9). Optimum dosing of antidepressants and antipsychotics is often controversial, but its importance cannot be overlooked (Article 4 & 5). Clozapine is once again drawing attention with its better comparative efficacy, this time demonstrating it in routine clinical practice (Article 7). We have a more reliable variable to look for while monitoring clinical improvement in patients on antidepressants (Article 8). New research raises questions about the efficacy of interventions for negative symptoms (Article 9) and that of anti-inflammatory therapies for psychiatric disorders (Article 10). 1. ANY NEW MEDICATIONS EMERGING FOR BIPOLAR DEPRESSION?

Comment évaluer l’effet curatif et/ou préventif des psychotropes ?

Proving the efficacy of a psychotropic drug is a medical, scientific and ethical need. Psychotropic drug development is now a highly complex process, which takes several years and which is very expensive. It involves multiple steps of preclinical and clinical pharmacological refinement and testing. Methodology of studies to prove curative or preventive effect of psychotropic drugs is well codified. Preclinical studies include pharmacokinetic data, toxicology and performance in various animal models of pathology. Clinical phases are centered on randomized controlled double blind trials for demonstrating efficacy and safety/tolerability. This methodology follows strict criteria to avoid bias and to prove internal and external validity of the results. All the results from randomized controlled trials or RCTs lead to different levels of evidence of Evidence-Based Medicine (EBM): gold standard is RCTs while the lowest reference is clinical case or expert opinion. However, it is possible to level criticism at these data issued from RCTs. The main matter is that studies do not reflect the healthcare reality in daily life. For these reasons, a real debate between evaluation of efficacy and effectiveness is acute. Effectiveness refers to the overall effects of psychotropic drugs in naturalistic conditions. Furthermore, analysis of costs and financial benefits are more and more important from social and economic points of view. Official agencies and health insurances look after them very carefully. This article deals with these issues and provides examples using data from the international literature. These examples are drawn from RCTs, naturalistic studies, meta-analysis, pharmaco-economic studies and concern neuroleptics, antipsychotics, antidepressants, and mood-stabilizers.

Psychotropic Drug Development Strategies that Target Neuropsychiatric Etiologies in Alzheimer's and Parkinson's Diseases.

Preclinical Research Neuropsychiatric symptoms are currently recognized as a common burden in patients suffering from Alzheimer's disease (AD), Parkinson's disease (PD), and many other neurodegenerative disorders. Earlier theories positing that these symptoms emerge predominantly in patients with late-stage disease have been largely dismissed. It is now generally accepted that many neuropsychiatric symptoms commonly manifest very early in neurodegenerative disease stages, and in many cases are even considered prodromal indicators. Despite intense research efforts, no reliable drug treatment strategies have been found for the neuropsychiatric symptoms associated with AD and PD. Among the medications commonly used at this stage, many present significant risks for patients in this particular cohort. Transcriptomic tools and proteomic profiling have clearly indicated that neurodegenerative diseases and their associated neuropsychiatric comorbidities are multifactorial in origin. As such, multiple-and in many cases divergent-disease etiologies lead to the neuropsychiatric symptoms associated with AD, PD, and other neurodegenerative disorders. The complexity of these pathways (initiated by a cascade of molecular events that involve several neurotransmitter systems) offer significant challenges to drug discovery efforts aimed at addressing these symptoms. In response to this complexity, a new paradigm has emerged that challenges the widely held assumption that "targeted" drug design is superior to the development of "multi-targeted" drugs as a strategy to address the neuropsychiatric symptoms associated with AD and PD. In this Overview, I offer an overview of drug discovery strategies and investigative drugs currently under development that address multiple CNS etiological targets associated with an array of neuropsychiatric symptoms. Drug Dev Res 77 : 458-468, 2016. © 2016 Wiley Periodicals, Inc.

New Horizons in Pediatric Psychopharmacology.

Preclinical Research Recent advances in pediatric psychopharmacology have been rather uneven. Increased use of psychotropic drugs among the pediatric population has raised concerns regarding their inappropriate use and safety. While clinical trials have been conducted on various pediatric psychopharmacological drugs, there has been an insignificant amount of importance to innovation in holistic treatment. A rational approach toward elucidating the various challenges would be contingent on the convergence of the development of novel efficacious psychotropic drugs with concrete conceptual frameworks and guidelines fostering enhanced outcomes. A research infrastructure concerning the relevance of the clinician's perspective, combining drugs with alternative therapies, the need for pediatric specific formulations and relevance of these in developing countries provides a basis on which innovative treatment/development can be constructed. The current commentary highlights these comprehensive and targeted treatment guidelines as aspects necessary for building the future of the field. Drug Dev Res 77 : 474-478, 2016. © 2016 Wiley Periodicals, Inc.

Involvement of 2-arachidonoylglycerol signaling in social challenge responding of male CD1 mice.

Endocannabinoids are strong modulators of emotionality and present a novel target for psychotropic drug development. Increasing evidence suggests that endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) affect behavior differentially. While the roles of anandamide have been investigated extensively, studies regarding the specific roles of 2-AG became possible only recently, and its involvement in social behaviors has not yet been studied. We studied the impact of 2-AG signaling on aggression as a first attempt to characterize the role of this endocannabinoid in social behaviors. 2-AG signaling was enhanced by the monoacylglycerol lipase inhibitor JZL184 (8, and 16mg/kg) in mice later submitted to the resident/intruder paradigm. JZL184 near completely abolished aggressiveness in residents and increased victimization (i.e., attacks by the opponent). Interestingly, the level of defensiveness remained unaltered, despite the large increase in bites received. The CB1 receptor blocker AM251 (0.5mg/kg) did not influence the effects of JZL184. In intruders, JZL184 near completely suppressed bites and offensive behavior in a fashion similar to residents, but it also increased agitation and defensiveness during, and the corticosterone response to, aggressive encounters. Experiments involving the corticosterone synthesis inhibitor metyrapone (30mg/kg) suggest that the suppression of biting and offensive behavior is directly influenced by JZL184, whereas increased agitation and defensiveness (seen in intruders only) are a secondary development of the stress-endocrine effects of JZL184. 2-AG signaling emerges as a surprisingly strong negative modulator of aggressiveness, which warrants further studies into its general role in social behavior and the target receptors involved.

The diminished pipeline for medications to treat mental health and substance use disorders.

Psychotropic drug development is perceived to be lagging behind other pharmaceutical development, even though there is a need for more effective psychotropic medications. This study examined the state of the current psychotropic drug pipeline and potential barriers to psychotropic drug development. The authors scanned the recent academic and "grey" literature to evaluate psychotropic drug development and to identify experts in the fields of psychiatry and substance use disorder treatment and psychotropic drug development. On the basis of that preliminary research, the authors interviewed six experts and analyzed drugs being studied for treatment of major psychiatric disorders in phase III clinical trials. Interviews and review of clinical trials of drugs in phase III of development confirmed that the psychotropic pipeline is slim and that a majority of the drugs in phase III trials are not very innovative. Among the barriers to development are incentives that encourage firms to focus on incremental innovation rather than take risks on radically new approaches. Other barriers include human brain complexity, failure of animal trials to translate well to human trials, and a drug approval threshold that is perceived as so high that it discourages development. Drivers of innovation in psychotropic drug development largely parallel those for other drugs, yet crucial distinctions have led to slowing psychotropic development after a period of innovation and growth. Various factors have acted to dry up the pipeline for psychotropic drugs, with expert opinion suggesting that in the near term, this trend is likely to continue.

Candidates, Innovation Missing From Psychotropic Drug Pipeline

Candidates, Innovation Missing From Psychotropic Drug Pipeline

Proteomic Investigation of the Hippocampus in Prenatally Stressed Mice Implicates Changes in Membrane Trafficking, Cytoskeletal, and Metabolic Function

Prenatal stress influences the development of the fetal brain and so contributes to the risk of the development of psychiatric disorders in later life. The hippocampus is particularly sensitive to prenatal stress, and robust abnormalities have been described in the hippocampus in schizophrenia and depression. The aim of this study was to determine whether prenatal stress is associated with distinct patterns of differential protein expression in the hippocampus using a validated mouse model. We therefore performed a comparative proteomic study assessing female hippocampal samples from 8 prenatally stressed mice and 8 control mice. Differential protein expression was assessed using 2-dimensional difference in gel electrophoresis and subsequent mass spectrometry. The observed changes in a selected group of differentially expressed proteins were confirmed by Western blotting. In comparison to controls, 47 protein spots (38 individual proteins) were found to be differentially expressed in the hippocampus of prenatally stressed mice. Functional grouping of these proteins revealed that prenatal stress influenced the expression of proteins involved in brain development, cytoskeletal composition, stress response, and energy metabolism. Western blotting was utilized to validate the changes in calretinin, hippocalcin, profilin-1 and the signal-transducing adaptor molecule STAM1. Septin-5 could not be validated via Western blotting due to methodological issues. Closer investigation of the validated proteins also pointed to an interesting role for membrane trafficking deficits mediated by prenatal stress. Our findings demonstrate that prenatal stress leads to altered hippocampal protein expression, implicating numerous molecular pathways that may provide new targets for psychotropic drug development.