Investigational drugs in recent clinical trials for treatment-resistant depression

ABSTRACT

Introduction: The authors describe the medications for treatment-resistant depression (TRD) in phase II/III of clinical development in the EU and USA and provide an opinion on how current treatment can be improved in the near future.

Areas covered: Sixty-two trials were identified in US and EU clinical trial registries that included six investigational compounds in recent phase III development and 12 others in recent phase II clinical trials. Glutamatergic agents have been the focus of many studies. A single intravenous dose of the glutamatergic modulator ketamine produces a robust and rapid antidepressant effect in persons with TRD; this effect continues to remain significant for 1 week. This observation was a turning point that opened the way for other, more selective glutamatergic modulators (intranasal esketamine, AVP-786, AVP-923, AV-101, and rapastinel). Of the remaining compounds, monoclonal antibodies open highly innovative therapeutic options, based on new pathophysiological approaches to depression.

Expert commentary: Promising new agents are emerging for TRD treatment. Glutamatergic modulators likely represent a very promising alternative to monoaminergic antidepressant monotherapy. We could see the arrival of the first robust and rapid acting antidepressant drug in the near future, which would strongly facilitate the ultimate goal of recovery in persons with TRD.

KEYWORDS:

• AV-101
• AVP-786
• brexpiprazole
• buprenorphine
• cariprazine
• clinical trials
• esketamine
• ketamine
• rapastinel
• treatment-resistant depression

Acknowledgments

The authors are grateful to Greg Panico (Janssen Research & Development, USA) for providing information about intranasal esketamine.

Declaration of interest

R.P. Garay is President of a non-profit association for therapeutic innovation (Craven, Villemoisson-sur-Orge, France). C.A. Zarate is listed as co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders. C.A. Zarate has assigned his patent rights to the U.S. government but will share a percent of royalties that may be received by the government. T. Charpeaud declares consultant activities and conferences for AstraZeneca, BMS, Janssen, Otsuka; invitation to Congress by Janssen, Lundbeck, Otsuka; and research activities for AMGEN, Janssen and Lilly. In the past 36 months L. Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: Acadia, Alexza, Alkermes, Allergan, AstraZeneca, Avanir, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, Valeant, Vanda. C.U. Correll has been a consultant and/or advisor to or has received honoraria from Alkermes, Forum, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, Medavante, Medscape, Neurocrine, Otsuka, Pfizer, ProPhase, Sunovion, Supernus, Takeda, and Teva. He has provided expert testimony for Bristol-Myers Squibb, Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck and Pfizer. He received grant support from Takeda. A Hameg is a member of a non-profit association for therapeutic innovation (Craven, Villemoisson-sur-Orge, France). P.M. Llorca declares grant support in addition to support for consultancy, expertise and honoraria for conferences from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Janssen-Cilag, Lundbeck A/S, Otsuka, Roche, and Sanofi Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.