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

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.

Key considerations for clinical trials in psychopharmacology

“…The excellent review of current efforts and issues in the field of psychopharmacology produced by Correll et al 1 does not, unfortunately, provide much that would convince skeptical decision makers that the fu-ture of psychopharmacology will look that much different from the past. I write from the perspective of selection of compounds and mechanisms for clinical devel opment as well as of implementation of clinical stud-ies across phases 1-3, both from the industry and the US National Institute of Mental Health (NIMH) vantage points.…”

“…The thoughtful review by Correll et al 1 ex­plores the status of drugs for mental disorders with new mechanisms of action cur­rently in testing, and details obstacles to developing such medications. The authors examined established clinical registries and identified ongoing clinical trials of agents that showed the most promise “as emerging from documented superiority over placebo, magnitude of the observed effects, and dem­onstration of requirements for safety and tol­erability”.…”

All levels of the translational spectrum must be targeted to advance psychopharmacology and improve patient outcomes

“…Correll et al 1 correctly state that many psychiatric disorders remain insufficiently treated despite advances in psychopharmacology, and attribute this to the limited knowledge of pathophysiology of these disorders, the lack of biological markers precluding tailored treatment selection, the few mechanistic targets for treatment development, and the challenges with clinical trial design and conduct. Here I address the chasms at the various levels of the translational spectrum that should be targeted through innovations in order to advance psychopharmacology and improve outcomes for patients.…”

Real changes can enhance information yield on novel psychopharmacologic agents

“…The excellent review of current efforts and issues in the field of psychopharmacology produced by Correll et al 1 does not, unfortunately, provide much that would convince skeptical decision makers that the future of psychopharmacology will look that much different from the past. I write from the perspective of selection of compounds and mechanisms for clinical devel­opment as well as of implementation of clinical stud­ies across phases 1‐3, both from the industry and the US National Institute of Mental Health (NIMH) vantage points.…”