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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| Veröffentlicht in: | Psychopharmacology 2021-05, Vol.238 (5), p.1279-1289 |
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| creator | 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. |
| description | 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
. |
| doi_str_mv | 10.1007/s00213-018-5134-y |
| format | Article |
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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
.</description><identifier>ISSN: 0033-3158</identifier><identifier>EISSN: 1432-2072</identifier><identifier>DOI: 10.1007/s00213-018-5134-y</identifier><identifier>PMID: 30536081</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Activation ; Adult ; Aminopyridines - pharmacology ; AMP ; Analysis ; Animal models ; Animals ; Behavior ; Benzamides - pharmacology ; Biomedical and Life Sciences ; Biomedicine ; Brain ; Brain - drug effects ; Brain mapping ; Cognition - drug effects ; Cognition Disorders - drug therapy ; Cognition Disorders - physiopathology ; Cognitive ability ; Control ; Cross-Over Studies ; Crossovers ; 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 tasks ; 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</subject><ispartof>Psychopharmacology, 2021-05, Vol.238 (5), p.1279-1289</ispartof><rights>The Author(s) 2018</rights><rights>COPYRIGHT 2021 Springer</rights><rights>Psychopharmacology is a copyright of Springer, (2018). All Rights Reserved. © 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c565t-3c82108b1c384e3ac13533eb5e03deff564c52ebeca7898cb5c4e9a80df751b83</citedby><cites>FETCH-LOGICAL-c565t-3c82108b1c384e3ac13533eb5e03deff564c52ebeca7898cb5c4e9a80df751b83</cites><orcidid>0000-0003-1095-9058</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00213-018-5134-y$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00213-018-5134-y$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,778,782,883,27907,27908,41471,42540,51302</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30536081$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gilleen, James</creatorcontrib><creatorcontrib>Farah, Yakub</creatorcontrib><creatorcontrib>Davison, Cate</creatorcontrib><creatorcontrib>Kerins, Sarah</creatorcontrib><creatorcontrib>Valdearenas, Lorena</creatorcontrib><creatorcontrib>Uz, Tolga</creatorcontrib><creatorcontrib>Lahu, Gez</creatorcontrib><creatorcontrib>Tsai, Max</creatorcontrib><creatorcontrib>Ogrinc, Frank</creatorcontrib><creatorcontrib>Reichenberg, Avi</creatorcontrib><creatorcontrib>Williams, Steve C.</creatorcontrib><creatorcontrib>Mehta, Mitul A.</creatorcontrib><creatorcontrib>Shergill, Sukhi S.</creatorcontrib><title>An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients</title><title>Psychopharmacology</title><addtitle>Psychopharmacology</addtitle><addtitle>Psychopharmacology (Berl)</addtitle><description>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
.</description><subject>Activation</subject><subject>Adult</subject><subject>Aminopyridines - pharmacology</subject><subject>AMP</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Behavior</subject><subject>Benzamides - pharmacology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain</subject><subject>Brain - drug effects</subject><subject>Brain mapping</subject><subject>Cognition - drug effects</subject><subject>Cognition Disorders - drug therapy</subject><subject>Cognition Disorders - physiopathology</subject><subject>Cognitive ability</subject><subject>Control</subject><subject>Cross-Over Studies</subject><subject>Crossovers</subject><subject>Cyclic AMP</subject><subject>Cyclopropanes - pharmacology</subject><subject>Data processing</subject><subject>Dosage</subject><subject>Dosage and administration</subject><subject>Double-Blind Method</subject><subject>Double-blind studies</subject><subject>Drug therapy</subject><subject>Episodic memory</subject><subject>Female</subject><subject>Functional magnetic resonance imaging</subject><subject>Humans</subject><subject>Language</subject><subject>Male</subject><subject>Memory</subject><subject>Memory tasks</subject><subject>Memory, Episodic</subject><subject>Memory, Short-Term - drug effects</subject><subject>Mental disorders</subject><subject>Mental task performance</subject><subject>Middle Aged</subject><subject>Neurosciences</subject><subject>Original Investigation</subject><subject>Patient outcomes</subject><subject>Patients</subject><subject>Pharmacology/Toxicology</subject><subject>Phosphodiesterase</subject><subject>Phosphodiesterase 4 Inhibitors - pharmacology</subject><subject>Phosphodiesterases</subject><subject>Placebos</subject><subject>Prefrontal cortex</subject><subject>Prefrontal Cortex - drug effects</subject><subject>Psychiatry</subject><subject>Psychological aspects</subject><subject>Roflumilast</subject><subject>Schizophrenia</subject><subject>Schizophrenia - drug therapy</subject><subject>Schizophrenia - physiopathology</subject><subject>Schizophrenics</subject><subject>Short term memory</subject><subject>Spatial memory</subject><subject>Statistical analysis</subject><issn>0033-3158</issn><issn>1432-2072</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9ks1u1DAUhSMEokPhAdggS2xYNMU_ceLZII0q_qRKbGBtOc7N5JaMHWynEJ6Ix8SjGUqLAFuWJfvcz_bxKYqnjJ4zSpuXkVLOREmZKiUTVbncK1asErzktOH3ixWlQpSCSXVSPIrxiuZWqephcSKoFDVVbFX82DgC3yYIuAOXzEh20KFFBySmuVuI70kagEyDj3l0CDFBMBHKiqAbsMXkwxkJvh_nHY4mpjPiHfnqw2d02wzb-bCUAUaToCNtMOiIsQmvMS3EuI7AhDFj7VGaoSTaAb_7aQjg0JDJJMw3i4-LB70ZIzw5zqfFpzevP168Ky8_vH1_sbksraxlKoVVnFHVMitUBcJYJqQQ0EqgooO-l3VlJYcWrGnUWtlW2grWRtGubyRrlTgtXh2409xmL2w-O5hRT9kgExbtDeq7Ow4HvfXXWtGai5plwIsjIPgvc_ZL7zBaGEfjwM9RcyYla_L30Sx9_of0ys_B5edpLlld00bJ5r8qJgUToua3WFszgkbX-3w7uz9ab2q5riSv-Z51_hdV7h3s0HoHPeb1OwXsUGCDjzFAf-MEo3ofQn0Ioc4h1PsQ6iXXPLtt4U3Fr9RlAT8IYt5yWwi_X_Rv6k-4zesL</recordid><startdate>20210501</startdate><enddate>20210501</enddate><creator>Gilleen, James</creator><creator>Farah, Yakub</creator><creator>Davison, Cate</creator><creator>Kerins, Sarah</creator><creator>Valdearenas, Lorena</creator><creator>Uz, Tolga</creator><creator>Lahu, Gez</creator><creator>Tsai, Max</creator><creator>Ogrinc, Frank</creator><creator>Reichenberg, Avi</creator><creator>Williams, Steve C.</creator><creator>Mehta, Mitul A.</creator><creator>Shergill, Sukhi S.</creator><general>Springer Berlin Heidelberg</general><general>Springer</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QR</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1095-9058</orcidid></search><sort><creationdate>20210501</creationdate><title>An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c565t-3c82108b1c384e3ac13533eb5e03deff564c52ebeca7898cb5c4e9a80df751b83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Activation</topic><topic>Adult</topic><topic>Aminopyridines - pharmacology</topic><topic>AMP</topic><topic>Analysis</topic><topic>Animal models</topic><topic>Animals</topic><topic>Behavior</topic><topic>Benzamides - pharmacology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain</topic><topic>Brain - drug effects</topic><topic>Brain mapping</topic><topic>Cognition - drug effects</topic><topic>Cognition Disorders - drug therapy</topic><topic>Cognition Disorders - physiopathology</topic><topic>Cognitive ability</topic><topic>Control</topic><topic>Cross-Over Studies</topic><topic>Crossovers</topic><topic>Cyclic AMP</topic><topic>Cyclopropanes - pharmacology</topic><topic>Data processing</topic><topic>Dosage</topic><topic>Dosage and administration</topic><topic>Double-Blind Method</topic><topic>Double-blind studies</topic><topic>Drug therapy</topic><topic>Episodic memory</topic><topic>Female</topic><topic>Functional magnetic resonance imaging</topic><topic>Humans</topic><topic>Language</topic><topic>Male</topic><topic>Memory</topic><topic>Memory tasks</topic><topic>Memory, Episodic</topic><topic>Memory, Short-Term - drug effects</topic><topic>Mental disorders</topic><topic>Mental task performance</topic><topic>Middle Aged</topic><topic>Neurosciences</topic><topic>Original Investigation</topic><topic>Patient outcomes</topic><topic>Patients</topic><topic>Pharmacology/Toxicology</topic><topic>Phosphodiesterase</topic><topic>Phosphodiesterase 4 Inhibitors - pharmacology</topic><topic>Phosphodiesterases</topic><topic>Placebos</topic><topic>Prefrontal cortex</topic><topic>Prefrontal Cortex - drug effects</topic><topic>Psychiatry</topic><topic>Psychological aspects</topic><topic>Roflumilast</topic><topic>Schizophrenia</topic><topic>Schizophrenia - drug therapy</topic><topic>Schizophrenia - physiopathology</topic><topic>Schizophrenics</topic><topic>Short term memory</topic><topic>Spatial memory</topic><topic>Statistical analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gilleen, James</creatorcontrib><creatorcontrib>Farah, Yakub</creatorcontrib><creatorcontrib>Davison, Cate</creatorcontrib><creatorcontrib>Kerins, Sarah</creatorcontrib><creatorcontrib>Valdearenas, Lorena</creatorcontrib><creatorcontrib>Uz, Tolga</creatorcontrib><creatorcontrib>Lahu, Gez</creatorcontrib><creatorcontrib>Tsai, Max</creatorcontrib><creatorcontrib>Ogrinc, Frank</creatorcontrib><creatorcontrib>Reichenberg, Avi</creatorcontrib><creatorcontrib>Williams, Steve C.</creatorcontrib><creatorcontrib>Mehta, Mitul A.</creatorcontrib><creatorcontrib>Shergill, Sukhi S.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Psychology</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Psychopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gilleen, James</au><au>Farah, Yakub</au><au>Davison, Cate</au><au>Kerins, Sarah</au><au>Valdearenas, Lorena</au><au>Uz, Tolga</au><au>Lahu, Gez</au><au>Tsai, Max</au><au>Ogrinc, Frank</au><au>Reichenberg, Avi</au><au>Williams, Steve C.</au><au>Mehta, Mitul A.</au><au>Shergill, Sukhi S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients</atitle><jtitle>Psychopharmacology</jtitle><stitle>Psychopharmacology</stitle><addtitle>Psychopharmacology (Berl)</addtitle><date>2021-05-01</date><risdate>2021</risdate><volume>238</volume><issue>5</issue><spage>1279</spage><epage>1289</epage><pages>1279-1289</pages><issn>0033-3158</issn><eissn>1432-2072</eissn><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
.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>30536081</pmid><doi>10.1007/s00213-018-5134-y</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-1095-9058</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Psychopharmacology, 2021-05, Vol.238 (5), p.1279-1289 |
| issn | 0033-3158 1432-2072 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Activation Adult Aminopyridines - pharmacology AMP Analysis Animal models Animals Behavior Benzamides - pharmacology Biomedical and Life Sciences Biomedicine Brain Brain - drug effects Brain mapping Cognition - drug effects Cognition Disorders - drug therapy Cognition Disorders - physiopathology Cognitive ability Control Cross-Over Studies Crossovers 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 tasks 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 |
| title | An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-16T18%3A40%3A55IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=An%20experimental%20medicine%20study%20of%20the%20phosphodiesterase-4%20inhibitor,%20roflumilast,%20on%20working%20memory-related%20brain%20activity%20and%20episodic%20memory%20in%20schizophrenia%20patients&rft.jtitle=Psychopharmacology&rft.au=Gilleen,%20James&rft.date=2021-05-01&rft.volume=238&rft.issue=5&rft.spage=1279&rft.epage=1289&rft.pages=1279-1289&rft.issn=0033-3158&rft.eissn=1432-2072&rft_id=info:doi/10.1007/s00213-018-5134-y&rft_dat=%3Cgale_pubme%3EA659452627%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2153133620&rft_id=info:pmid/30536081&rft_galeid=A659452627&rfr_iscdi=true |