King's College London

Research portal

The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial

Research output: Contribution to journalArticlepeer-review

James Gilleen, Judith Nottage, Farah Yakub, Sarah Kerins, Lorena Valdearenas, Tolga Uz, Gez Lahu, Max Tsai, Frank Ogrinc, Steve C. Williams, Dominic Ffytche, Mitul A. Mehta, Sukhi S. Shergill

Original languageEnglish
Pages (from-to)15-22
Number of pages8
JournalJournal of Psychopharmacology
Volume35
Issue number1
DOIs
Accepted/In press1 Jan 2020
PublishedJan 2021

Bibliographical note

Funding Information: We thank South London and Maudsley NHS Foundation Trust for supporting participant recruitment. We would also like to acknowledge and thank the patients who participated for the time and effort they gave to the study. The views expressed are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research (NIHR) or the Department of Health. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Takeda Pharma A/S, London. We also acknowledge the on-going support from the NIHR-Wellcome Trust King?s Clinical Research Facility and the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King?s College London. Funding Information: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SSS has received grant funding for clinical trials and/or honoraria for educational input from EnVivo Pharmaceuticals, Takeda, AbbVie and Janssen Pharmaceuticals. He is supported by a European Research Council Consolidator Award (Grant Number 311686) and the NIHR Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. MAM has acted as a consultant for Lundbeck and FORUM pharmaceuticals in the past 5 years. He also has or has held research funding from Shire, Roche, Lundbeck and Takeda in the past 5 years. JG has acted as consultant for Quintiles CRO Ltd and Takeda Pharma A/S in the past 5 years. YF, CD, SK, LV, AR and SCW have no disclosures or conflicts of interest to report. TU, GL and FO are employees of Takeda Development Center Americas, Inc., Chicago, USA MT is employed by Eli Lilly, Indianapolis, USA. Funding Information: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Takeda Pharma A/S, London. We also acknowledge the on-going support from the NIHR-Wellcome Trust King’s Clinical Research Facility and the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Publisher Copyright: © The Author(s) 2020. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Background: Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia. Aims: Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia. Methods: Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis. Results: Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity (p=0.04) and working memory-related theta oscillations (p=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers. Conclusions: The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454