Preliminary evidence for the PDE4-inhibitor, roflumilast, in ameliorating cognitive flexibility deficits in patients with schizophrenia

Nick Livingston, James Gilleen, Peter Hawkins, Sukhi Shergill, Mitul Mehta

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Background: Cognitive flexibility deficits are present in patients with schizophrenia and are strong predictors of functional outcome but as yet these have no pharmacological treatments.
Objectives: Based on preclinical findings, this study investigated whether the phosphodiesterase type 4 inhibitor, roflumilast, can improve impaired cognitive flexibility performance, and examined the underlying functional brain activity in patients with schizophrenia.
Methods: This study was a within-subject, randomised, double-blind, placebo-controlled study using an fMRI-optimised version of the Intradimensional/Extradimensional (ID/ED) task in 10 patients with schizophrenia after receiving placebo, 100µg or 250µg roflumilast for 8 consecutive days- given in a counterbalanced order. Data from an additional fMRI ID/ED study of 18 healthy controls on placebo was included to contextualise schizophrenia-related deficits and drug effects. Behavioural performance and functional scans were analysed to investigate the cognitive cost and neural correlates of solution search, attentional set-shifting and reversal learning across groups and drug conditions. Functional analyses included a-priori-driven ROI analysis of the dorsal frontoparietal attention network (dFPN).
Results: Patients with schizophrenia on placebo demonstrated similar activity to the healthy comparison group across the dFPN for solution search, despite broad deficits in task performance. Conversely, patients’ poorer attentional set-shifting was associated with reduced activity in left ventrolateral prefrontal cortex and posterior parietal cortex (PPC). Additionally, their poorer reversal learning performance was associated with reduced activity in the left dorsolateral prefrontal cortex (DLPFC). During solution search, 100µg roflumilast reduced activity in left orbitofrontal cortex (OFC), right DLPFC and bilateral PPC, which was associated with improvement in formation of attentional sets. During attentional set-shifting and reversal learning, 250µg roflumilast exhibited a large drug-effect across the network, ameliorating ROI deficits observed on placebo, although this was not associated with any behavioural performance improvement.
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 future larger studies to test roflumilast’s role in improving cognitive flexibility deficits in patients with schizophrenia.

© 2021, SAGE Journals. This is an author produced version of a paper published in
Journal of Psychopharmacology uploaded in accordance with the publisher’s self- archiving policy. The final published version (version of record) is available online at the link. Some minor differences between this version and the final published version may remain. We suggest you refer to the final published version should you wish to cite from it.
Original languageEnglish
Publication statusPublished - 28 Apr 2021

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