The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update

ABSTRACT

Introduction: Despite recent advances in Alzheimer’s disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile.

Areas covered: 5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I–III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD.

Expert opinion: Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.

KEYWORDS:

• Alzheimer’s disease
• 5-HT6 receptor
• expert opinion
• pharmacotherapy
• neurotransmitter
• symptomatic therapy

Article highlights

• The 5-HT6 receptor has been investigated as a promising target for the development of a new symptomatic treatment for Alzheimer’s disease (AD), to be added to the currently FDA-approved therapies: cholinesterase inhibitors and the NMDA-receptor antagonist memantine.

• Most research has been conducted with selective 5-HT6 receptor antagonists believed to primarily modulate glutamate and GABA levels, and to consequently increase brain concentrations of dopamine, acetylcholine and norepinephrine, all of which are found to be compromised in AD.

• Despite promising preclinical data and phase-II study (the LADDER trial) with idalopirdine, three large randomized placebo-controlled phase-III trials failed to demonstrate a positive effect on cognition, when used as an adjunct treatment to cholinesterase inhibitors in patients with mild–moderate AD (STARSHINE, STARBEAM, and STARBRIGHT)

• Several phase-II trials with another selective 5-HT6 receptor antagonist, intepirdine, have yielded conflicting results with respect to improvements in cognition and functionality in patients with mild–moderate AD. The phase-III MINDSET trial’s recently released results were however disappointing.

• SUVN-502 is a third 5-HT6 receptor antagonist currently being investigated in phase-IIa trial, as an adjunct to combination therapy (cholinesterase inhibitor and memantine) in patients with moderate AD.

• Repeated failures with 5-HT6 receptor antagonist compounds can’t be fully explained by methodological problems, related to dosing, inclusion criteria or pharmacokinetic considerations, as the 5-HT6 receptor functionality is very complex and not well-elucidated as of yet.

• Future studies should focus more on the effect of different ligands binding to this receptor, as 5-HT6 receptor agonists have been also shown to have pro-cognitive effects. Trials with partial or inverse agonists may yield more promising cognitive enhancing effects.

This box summarizes key points contained in the article.

Declaration of Interest

G. T. Grossberg served as a consultant for Acadia, Allergan, Avanir, Axovant, GE, Genentech, Lundbeck, Novartis, Otsuka, Roche and Takeda pharmaceuticals, received research support from Cognoptix, Janssen and NIH, provided safety monitoring for EryDel, Merck, Newron and is on the Speaker’s Bureau for Acadia. 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.