Investigational drugs for treating agitation in persons with dementia

ABSTRACT

Introduction: Agitation is common and distressing in persons with dementia, but safe, effective treatments remain elusive. In this review, the authors describe investigational compounds in ongoing or recently completed clinical trials for this indication and provide an opinion on how they may meet current therapeutic needs.

Areas covered: Phase II and phase III clinical trials for agitation in persons with dementia were searched in US and EU clinical trial registries and in the medical literature for the period January 2013-February 2016

Expert opinion: The authors searches identified 24 recent clinical trials investigating new treatments for agitation in persons with dementia. Candidate drugs in phase III development included the antipsychotic brexpiprazole, the antidepressant citalopram, the novel compound AVP-786 (deuterated-dextromethorphan/quinidine combination) and the cannabinoid nabilone. Of the compounds in phase II clinical trials, ELND005 (scyllo-inositol) is intended to progress into phase III development, based on evidence from a subgroup analysis and biomarker data. After many years without an FDA/EMA (Food and Drug Administration/European Medicines Agency) approved medication to treat agitation in persons with dementia, we may see the arrival of the first approved drug in the near future.

KEYWORDS:

• Agitation
• Alzheimer’s disease
• aripiprazole
• AVP-786
• brexpiprazole
• citalopram
• dementia
• ELND005
• eltoprazine
• nabilone

Article highlights

• Dementia is becoming a major threat to public health as the world’s population ages. No FDA (Food and Drug Administration)- or EMA (European Medicines Agency)-approved pharmacotherapies are available for this condition.

• Off-label psychotropic medications including atypical antipsychotics, anti-depressants, benzodiazepines and anti-convulsants are frequently used to manage agitation in persons with dementia. These currently prescribed treatments have modest efficacy and their use can produce harmful side effects, including death.

• Sixteen recent phase III clinical trials were investigating new treatments for agitation in dementia. The antidepressant citalopram significantly attenuated patient’s agitation, but cardiac adverse effects may limit its application. Better-tolerated and more potent antidepressants, like ketamine deserve investigation.

• Other candidate drugs in phase III development included the antipsychotic brexpiprazole, the novel compound AVP-786 (deuterated-dextromethorphan/quinidine combination) and the cannabinoid nabilone.

• Of the compounds in phase II clinical trials, the inositol isomer ELND005 significantly reduced the emergence of NPS (neuropsychiatric symptoms) in patients with mild to moderate symptoms.

This box summarizes key points contained in the article.

Acknowledgments

We are grateful to Michel Bourin (University of Nantes, France) for providing information about anti-aggressive compounds and sedative mechanisms in animal models. We also thank Catherine Weiss (Director, Global Medical Affairs, Otsuka, USA) for providing information concerning clinical trials with brexpiprazole and aripiprazole.

Declaration of interest

RP Garay is the president of and I Cavero a member of Craven, Villemoisson-sur-Orge, France, a non-profit association for therapeutic innovation. 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 and Company, Forum, Genentech, Janssen Pharmaceuticals, Jazz, Lundbeck A/S, Merck & Co, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer Inc, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, Valeant, Vanda. GT Grossberg declares consultancy for Accera, Avanir, Forest/Actavis/Allergan, GE Healthcare, Genentech, Lundbeck A/S, Novartis, Otsuka, Roche and Takeda; research support from Accera, Forest and Noven; and was member of the Safety Monitoring Committees of EryDel, Merck & Co and Newron. PM Llorca declares grant support in addition to support for consultancy, expertise and honoraria for conferences from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Forum, Janssen Pharmaceuticals, Lundbeck A/S, Otsuka, Roche, Sanofi, Servier, Takeda and Teva. 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.