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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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| Authors: | Christoph U Correll Marco Solmi Samuele Cortese Maurizio Fava Mikkel Højlund Helena C Kraemer Roger S McIntyre Daniel S Pine Lon S Schneider John M Kane |
| Institution: | 1. Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany
Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA;2. Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada Department of Mental Health, Ottawa Hospital, Ottawa, ON, Canada Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ottawa, ON, Canada School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK;3. Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK Solent NHS Trust, Southampton, UK Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York, NY, USA;4. Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;5. Department of Public Health, Clinical Pharmacology, Pharmacy and Environmental Medicine, University of Southern Denmark, Odense, Denmark Mental Health Services in the Region of Southern Denmark, Department of Psychiatry Aabenraa, Aabenraa, Denmark;6. Department of Psychiatry and Behavioral Sciences, Stanford University, Cupertino, CA, USA;7. Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada Department of Psychiatry, University of Toronto, Toronto, ON, Canada Department of Pharmacology, University of Toronto, Toronto, ON, Canada Brain and Cognition Discovery Foundation, Toronto, ON, Canada;8. Section on Developmental Affective Neuroscience, National Institute of Mental Health, Bethesda, MD, USA;9. 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;10. Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA |
| Abstract: | 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. |
| Keywords: | Psychopharmacology clinical trials design methodology novel mechanisms of action schizophrenia bipolar disorder major depressive disorder anxiety disorders trauma-related disorders substance use disorders dementia |