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

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, w...

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Published inPsychopharmacology Vol. 238; no. 5; pp. 1279 - 1289
Main Authors Gilleen, James, Farah, Yakub, Davison, Cate, Kerins, Sarah, Valdearenas, Lorena, Uz, Tolga, Lahu, Gez, Tsai, Max, Ogrinc, Frank, Reichenberg, Avi, Williams, Steve C., Mehta, Mitul A., Shergill, Sukhi S.
Format Journal Article
LanguageEnglish
Published Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2021
Springer
Springer Nature B.V
Subjects
Adult
Aminopyridines - pharmacology
AMP
Analysis
Animal models
Animals
Behavior
Benzamides - pharmacology
Biomedical and Life Sciences
Biomedicine
Brain - drug effects
Brain mapping
Cognition - drug effects
Cognition Disorders - drug therapy
Cognition Disorders - physiopathology
Cognitive ability
Control
Cross-Over Studies
Cyclic AMP
Cyclopropanes - pharmacology
Data processing
Dosage
Dosage and administration
Double-Blind Method
Double-blind studies
Drug therapy
Episodic memory
Female
Functional magnetic resonance imaging
Humans
Language
Male
Memory
Memory, Episodic
Memory, Short-Term - drug effects
Mental disorders
Mental task performance
Middle Aged
Neurosciences
Original Investigation
Patient outcomes
Patients
Pharmacology/Toxicology
Phosphodiesterase
Phosphodiesterase 4 Inhibitors - pharmacology
Phosphodiesterases
Placebos
Prefrontal cortex
Prefrontal Cortex - drug effects
Psychiatry
Psychological aspects
Roflumilast
Schizophrenia
Schizophrenia - drug therapy
Schizophrenia - physiopathology
Schizophrenics
Short term memory
Spatial memory
Statistical analysis
United Kingdom
fMRI
PDE4 inhibition
PDE4
Memory
CIAS
Schizophrenia
Cognition
Cognitive enhancement
Roflumilast
Online AccessGet full text

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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 .
AbstractList 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 [mu]g 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 [mu]g 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.
Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. 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. 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. 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). 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. NCT02079844 .
RationaleSchizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits.ObjectivesBased 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.MethodsThis 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.ResultsVerbal 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).ConclusionsResults 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 registrationNCT02079844.
Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. 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. 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 [mu]g 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. Verbal memory was significantly improved under 250 [mu]g 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). Trial registration
Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits.RATIONALESchizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits.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.OBJECTIVESBased 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.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.METHODSThis 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.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).RESULTSVerbal 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).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.CONCLUSIONSResults 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.NCT02079844 .TRIAL REGISTRATIONNCT02079844 .
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 .
Audience Academic
Author Ogrinc, Frank
Williams, Steve C.
Mehta, Mitul A.
Farah, Yakub
Davison, Cate
Tsai, Max
Kerins, Sarah
Lahu, Gez
Reichenberg, Avi
Valdearenas, Lorena
Gilleen, James
Shergill, Sukhi S.
Uz, Tolga
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  orcidid: 0000-0003-1095-9058
  surname: Gilleen
  fullname: Gilleen, James
  email: james.gilleen@roehampton.ac.uk
  organization: Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, Department of Psychology, University of Roehampton
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  organization: Takeda Development Center Americas, Inc
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  fullname: Lahu, Gez
  organization: Takeda Development Center Americas, Inc
– sequence: 8
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  surname: Tsai
  fullname: Tsai, Max
  organization: Eli Lilly and Company
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  surname: Ogrinc
  fullname: Ogrinc, Frank
  organization: Takeda Development Center Americas, Inc
– sequence: 10
  givenname: Avi
  surname: Reichenberg
  fullname: Reichenberg, Avi
  organization: Department of Psychiatry, Icahn School of Medicine at Mount Sinai
– sequence: 11
  givenname: Steve C.
  surname: Williams
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  organization: Department of Neuroimaging, IoPPN, Kings College London
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  organization: Department of Neuroimaging, IoPPN, Kings College London
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  givenname: Sukhi S.
  surname: Shergill
  fullname: Shergill, Sukhi S.
  organization: Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30536081$$D View this record in MEDLINE/PubMed
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IsDoiOpenAccess true
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Issue 5
Keywords fMRI
PDE4 inhibition
PDE4
Memory
CIAS
Schizophrenia
Cognition
Cognitive enhancement
Roflumilast
Language English
License Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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Snippet Rationale Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. Objectives Based on...
Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. Based on animal models, we...
Rationale Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. Objectives Based on...
Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. Based on animal models, we...
RationaleSchizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits.ObjectivesBased on...
Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits.RATIONALESchizophrenia is...
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StartPage 1279
SubjectTerms Adult
Aminopyridines - pharmacology
AMP
Analysis
Animal models
Animals
Behavior
Benzamides - pharmacology
Biomedical and Life Sciences
Biomedicine
Brain - drug effects
Brain mapping
Cognition - drug effects
Cognition Disorders - drug therapy
Cognition Disorders - physiopathology
Cognitive ability
Control
Cross-Over Studies
Cyclic AMP
Cyclopropanes - pharmacology
Data processing
Dosage
Dosage and administration
Double-Blind Method
Double-blind studies
Drug therapy
Episodic memory
Female
Functional magnetic resonance imaging
Humans
Language
Male
Memory
Memory, Episodic
Memory, Short-Term - drug effects
Mental disorders
Mental task performance
Middle Aged
Neurosciences
Original Investigation
Patient outcomes
Patients
Pharmacology/Toxicology
Phosphodiesterase
Phosphodiesterase 4 Inhibitors - pharmacology
Phosphodiesterases
Placebos
Prefrontal cortex
Prefrontal Cortex - drug effects
Psychiatry
Psychological aspects
Roflumilast
Schizophrenia
Schizophrenia - drug therapy
Schizophrenia - physiopathology
Schizophrenics
Short term memory
Spatial memory
Statistical analysis
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Title An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients
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