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

Nicholas R Livingston,Sukhi S Shergill,Lorena Valdearenas,Peter Ct Hawkins,Mitul A Mehta,James Gilleen,Rong Ye

doi:10.1177/02698811211000778

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.

Highlights

Schizophrenia is typically characterised by positive and negative symptoms (American Psychiatric Association, 2013), but patients display cognitive deficits, for which there are no approved targeted pharmacological treatments
One of the most pronounced cognitive deficits observed in schizophrenia is in the domain of attention, with meta-analyses reporting a large effect size (−0.8 to −1.4) of poorer performance in drug naïve (Fatouros-Bergman et al, 2014), first-episode (Mesholam-Gately et al, 2009; Zhang et al, 2019) and chronic (Bora et al, 2017) schizophrenia patients compared to healthy controls
This study used an functional magnetic resonance imaging (fMRI)-optimised version of the Intradimensional/ Extradimensional (ID/ED) attentional set-shifting task (Hampshire and Owen, 2006) to investigate the ability of the PDE type-4 (PDE4) inhibitor, roflumilast, to improve attentional set-shifting in patients with schizophrenia

Summary

Introduction

Schizophrenia is typically characterised by positive and negative symptoms (American Psychiatric Association, 2013), but patients display cognitive deficits, for which there are no approved targeted pharmacological treatments. There are two types of set-shift: within the same dimension, termed an intradimensional (ID) shift (e.g. from a building to a different building), or between dimensions, termed an extradimensional (ED) shift (e.g. building to face), with the latter typically requiring more trials to successfully solve (Roberts et al, 1988) This task has been validated in lesion studies (Dias et al, 1996) and neuroimaging studies (Hampshire and Owen, 2006), is sensitive to pharmacological modulation (Tait et al, 2014), and has been extensively used to examine set-shifting deficits in schizophrenia (Waltz, 2017). 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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