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

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

doi:10.1177/0269881120946300

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

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.

Original language	English
Pages (from-to)	15-22
Number of pages	8
Journal	Journal of Psychopharmacology
Volume	35
Issue number	1
DOIs	https://doi.org/10.1177/0269881120946300
Publication status	Published - Jan 2021

Keywords

cognition
EEG
PDE4
PDE4 inhibition
roflumilast
Schizophrenia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1177/0269881120946300

Cite this

Gilleen, J., Nottage, J., Yakub, F., Kerins, S., Valdearenas, L., Uz, T., Lahu, G., Tsai, M., Ogrinc, F., Williams, S. C., Ffytche, D., Mehta, M. A., & Shergill, S. S. (2021). The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial. Journal of Psychopharmacology, 35(1), 15-22. https://doi.org/10.1177/0269881120946300

@article{116e301ee91f4dc0b240649cef63b272,

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

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.",

keywords = "cognition, EEG, PDE4, PDE4 inhibition, roflumilast, Schizophrenia",

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

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{\textquoteright}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{\textquoteright}s Clinical Research Facility and the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. Publisher Copyright: {\textcopyright} The Author(s) 2020. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jan,

doi = "10.1177/0269881120946300",

language = "English",

volume = "35",

pages = "15--22",

journal = "Journal of Psychopharmacology",

issn = "0269-8811",

publisher = "SAGE Publications Ltd STM",

number = "1",

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Gilleen, J , Nottage, J , Yakub, F , Kerins, S, Valdearenas, L, Uz, T, Lahu, G, Tsai, M, Ogrinc, F, Williams, SC , Ffytche, D , Mehta, MA & Shergill, SS 2021, 'The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial', Journal of Psychopharmacology, vol. 35, no. 1, pp. 15-22. https://doi.org/10.1177/0269881120946300

TY - JOUR

T1 - The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia

T2 - A randomised controlled trial

AU - Gilleen, James

AU - Nottage, Judith

AU - Yakub, Farah

AU - Kerins, Sarah

AU - Valdearenas, Lorena

AU - Uz, Tolga

AU - Lahu, Gez

AU - Tsai, Max

AU - Ogrinc, Frank

AU - Williams, Steve C.

AU - Ffytche, Dominic

AU - Mehta, Mitul A.

AU - Shergill, Sukhi S.

N1 - 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.

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

KW - cognition

KW - EEG

KW - PDE4

KW - PDE4 inhibition

KW - roflumilast

KW - Schizophrenia

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U2 - 10.1177/0269881120946300

DO - 10.1177/0269881120946300

M3 - Article

AN - SCOPUS:85089991712

SN - 0269-8811

VL - 35

SP - 15

EP - 22

JO - Journal of Psychopharmacology

JF - Journal of Psychopharmacology

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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