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Clinical Trial
. 2021 May;238(5):1279-1289.
doi: 10.1007/s00213-018-5134-y. Epub 2018 Dec 8.

An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients

James Gilleen  1   2 , Yakub Farah  3 , Cate Davison  4 , Sarah Kerins  3 , Lorena Valdearenas  3   5 , Tolga Uz  6 , Gez Lahu  6 , Max Tsai  7 , Frank Ogrinc  6 , Avi Reichenberg  8 , Steve C Williams  9 , Mitul A Mehta  9 , Sukhi S Shergill  3
Affiliations
Clinical Trial

An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients

James Gilleen et al. Psychopharmacology (Berl). 2021 May.

Abstract

Rationale: Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits.

Objectives: Based on animal models, we investigated the potential for roflumilast, a selective inhibitor of phosphodiesterase type 4 (PDE4), to improve cognition, which may act by increasing intracellular cyclic adenosine monophosphate in brain regions underlying cognitive deficits in schizophrenia.

Methods: This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 μg daily) with 14 days of washout between treatments. The primary endpoints were dorsolateral prefrontal cortex (DLPFC) activation during a visuospatial working memory task measured with fMRI on dosing day 8 and verbal memory and working memory performance change from baseline to day 8. Least square mean change scores were calculated for behavioural outcomes; fMRI data were analysed in SPM12 with bilateral DLPFC as regions of interest.

Results: Verbal memory was significantly improved under 250 μg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03).

Conclusions: Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia.

Trial registration: NCT02079844 .

Keywords: CIAS; Cognition; Memory; PDE4; Roflumilast; Schizophrenia; fMRI; ‘Cognitive enhancement’; ‘PDE4 inhibition’.

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Conflict of interest statement

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 National Institute for Health Research (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 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 in the past 5 years. JG has acted as consultant for Quintiles CRO Ltd. 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, U.S.A.MT is employed by Eli Lilly, Indianapolis, USA.

Figures

Fig. 1
Fig. 1
Showing study schedule
Fig. 2
Fig. 2
Showing task schematic for the Dot Task
Fig. 3
Fig. 3
Showing DOT task fMRI results. a showing brain regions where activity was lower with 250 μg (green; a priori ROIs in yellow). b showing extracted beta coefficients of activity for the peak voxel within the a priori ROI at each drug dose (n = 10). c is a histogram showing the LS mean difference from placebo and 95% confidence intervals for all 13 participants who completed the DOT task
See this image and copyright information in PMC

References

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