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Preliminary evidence for the phosphodiesterase type-4 inhibitor, roflumilast, in ameliorating cognitive flexibility deficits in patients with schizophrenia

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)1099-1110
Number of pages12
JournalJournal of Psychopharmacology
Volume35
Issue number9
Early online date28 Apr 2021
DOIs
E-pub ahead of print28 Apr 2021
PublishedSep 2021

Bibliographical note

Funding Information: The author(s) 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 SLAM NHS Foundation Trust and King’s College London. MAM has acted as a consultant for Cambridge Cognition, Lundbeck and FORUM pharmaceuticals in the past 5 years. He also has or has held research funding from Shire, Roche, Lundbeck and Takeda Pharmaceuticals in the past 5 years. JG has acted as consultant for Quintiles CRO Ltd and Takeda Pharmaceuticals. NRL, PCTH, RY and LV have no disclosures or conflicts of interest to report. Funding Information: The authors would like to thank all of the participants for their time and contribution to the previous studies. They would also like to thank the National Institute for Health Research (NIHR)-Wellcome Trust King?s Clinical Research Facility, the NIHR Biomedical Research Centre at South London and Maudsley (SLaM) NHS Foundation Trust and King?s College London for their constant support. Additionally, the authors wish to thank Tolga Uz for supporting this research while at Takeda Pharmaceuticals. The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The collection of Dataset 1 was supported by Departmental funds and the collection of Dataset 2 was funded by Takeda Pharmaceutical Company Ltd (ROF-SCHZ_106). YR was supported by a King?s-China Scholarship Council Studentship. This paper represents independent research part funded by the National Institute for Health Research (NIHR), Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King?s College London that supports MAM. Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The collection of Dataset 1 was supported by Departmental funds and the collection of Dataset 2 was funded by Takeda Pharmaceutical Company Ltd (ROF-SCHZ_106). YR was supported by a King’s-China Scholarship Council Studentship. This paper represents independent research part funded by the National Institute for Health Research (NIHR), Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London that supports MAM. Funding Information: The authors would like to thank all of the participants for their time and contribution to the previous studies. They would also like to thank the National Institute for Health Research (NIHR)-Wellcome Trust King’s Clinical Research Facility, the NIHR Biomedical Research Centre at South London and Maudsley (SLaM) NHS Foundation Trust and King’s College London for their constant support. Additionally, the authors wish to thank Tolga Uz for supporting this research while at Takeda Pharmaceuticals. Publisher Copyright: © The Author(s) 2021. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Background: Cognitive flexibility deficits are present in patients with schizophrenia and are strong predictors of functional outcome but, as yet, have no pharmacological treatments. Aims: The purpose of this study was to investigate whether the phosphodiesterase type-4 inhibitor, roflumilast, can improve cognitive flexibility performance and functional brain activity in patients with schizophrenia. Methods: This was a within-subject, randomised, double-blind, placebo-controlled, three-period crossover study using a version of the Intradimensional/Extradimensional (ID/ED) task, optimised for functional magnetic resonance imaging (fMRI), in 10 patients with schizophrenia who were scanned after receiving placebo, 100 µg or 250 µg roflumilast for 8 consecutive days. Data from an additional fMRI ID/ED study of 18 healthy participants on placebo was included to contextualise the schizophrenia-related performance and activations. The fMRI analyses included a priori driven region of interest (ROI) analysis of the dorsal frontoparietal attention network. Results: Patients on placebo demonstrated broad deficits in task performance compared to the healthy comparison group, accompanied by preserved network activity for solution search, but reduced activity in left ventrolateral prefrontal cortex (VLPFC) and posterior parietal cortex for attentional set-shifting and reduced activity in left dorsolateral prefrontal cortex (DLPFC) for reversal learning. These ROI deficits were ameliorated by 250 µg roflumilast, whereas during solution search 100 µg roflumilast reduced activity in the left orbitofrontal cortex, right DLPFC and bilateral PPC, which was associated with an improvement in formation of attentional sets. Conclusions: The results suggest roflumilast has dose-dependent cognitive enhancing effects on the ID/ED task in patients with schizophrenia, and provides sufficient support for larger studies to test roflumilast’s role in improving cognitive flexibility deficits in this clinical population.

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