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      The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de‐risk trial programmes of novel agents

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          Abstract

          <p class="first" id="d4715222e360">Despite considerable progress in pharmacotherapy over the past seven decades, many mental disorders remain insufficiently treated. This situation is in part due to the limited knowledge of the pathophysiology of these disorders and the lack of biological markers to stratify and individualize patient selection, but also to a still restricted number of mechanisms of action being targeted in monotherapy or combination/augmentation treatment, as well as to a variety of challenges threatening the successful development and testing of new drugs. In this paper, we first provide an overview of the most promising drugs with innovative mechanisms of action that are undergoing phase 2 or 3 testing for schizophrenia, bipolar disorder, major depressive disorder, anxiety and trauma-related disorders, substance use disorders, and dementia. Promising repurposing of established medications for new psychiatric indications, as well as variations in the modulation of dopamine, noradrenaline and serotonin receptor functioning, are also considered. We then critically discuss the clinical trial parameters that need to be considered in depth when developing and testing new pharmacological agents for the treatment of mental disorders. Hurdles and perils threatening success of new drug development and testing include inadequacy and imprecision of inclusion/exclusion criteria and ratings, sub-optimally suited clinical trial participants, multiple factors contributing to a large/increasing placebo effect, and problems with statistical analyses. This information should be considered in order to de-risk trial programmes of novel agents or known agents for novel psychiatric indications, increasing their chances of success. </p>

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          Most cited references237

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          Sample Selection Bias as a Specification Error

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            Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis

            Summary Background Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. Methods We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. Findings We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. Interpretation All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. Funding National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.
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              Trial of Psilocybin versus Escitalopram for Depression

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                Author and article information

                Journal
                World Psychiatry
                World Psychiatry
                Wiley
                1723-8617
                2051-5545
                February 2023
                January 14 2023
                February 2023
                : 22
                : 1
                : 48-74
                Affiliations
                [1 ]Department of Child and Adolescent Psychiatry Charité Universitätsmedizin Berlin Berlin Germany
                [2 ]Department of Psychiatry Zucker Hillside Hospital, Northwell Health Glen Oaks NY USA
                [3 ]Department of Psychiatry and Molecular Medicine Zucker School of Medicine at Hofstra/Northwell Hempstead NY USA
                [4 ]Center for Psychiatric Neuroscience Feinstein Institute for Medical Research Manhasset NY USA
                [5 ]Department of Psychiatry University of Ottawa Ottawa ON Canada
                [6 ]Department of Mental Health Ottawa Hospital Ottawa ON Canada
                [7 ]Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program University of Ottawa Ottawa ON Canada
                [8 ]School of Epidemiology and Public Health, Faculty of Medicine University of Ottawa Ottawa ON Canada
                [9 ]Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences University of Southampton Southampton UK
                [10 ]Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine University of Southampton Southampton UK
                [11 ]Solent NHS Trust Southampton UK
                [12 ]Division of Psychiatry and Applied Psychology, School of Medicine University of Nottingham Nottingham UK
                [13 ]Hassenfeld Children's Hospital at NYU Langone New York University Child Study Center New York NY USA
                [14 ]Depression Clinical and Research Program Massachusetts General Hospital, Harvard Medical School Boston MA USA
                [15 ]Department of Public Health, Clinical Pharmacology, Pharmacy and Environmental Medicine University of Southern Denmark Odense Denmark
                [16 ]Mental Health Services in the Region of Southern Denmark Department of Psychiatry Aabenraa Aabenraa Denmark
                [17 ]Department of Psychiatry and Behavioral Sciences Stanford University Cupertino CA USA
                [18 ]Mood Disorders Psychopharmacology Unit University Health Network Toronto ON Canada
                [19 ]Institute of Medical Science University of Toronto Toronto ON Canada
                [20 ]Canadian Rapid Treatment Center of Excellence Mississauga ON Canada
                [21 ]Department of Psychiatry University of Toronto Toronto ON Canada
                [22 ]Department of Pharmacology University of Toronto Toronto ON Canada
                [23 ]Section on Developmental Affective Neuroscience National Institute of Mental Health Bethesda MD USA
                [24 ]Department of Psychiatry and Behavioral Sciences, and Department of Neurology, Keck School of Medicine, and L. Davis School of Gerontology University of Southern California Los Angeles CA USA
                Article
                10.1002/wps.21056
                9840514
                36640403
                2b8df951-4cbd-4a9d-9b11-4140516fc8b2
                © 2023

                http://onlinelibrary.wiley.com/termsAndConditions#vor

                http://doi.wiley.com/10.1002/tdm_license_1.1

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