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

James Gilleen, Yakub Farah, Cate Davison, Sarah Kerins, Lorena Valdearenas, Tolga Uz, Gez Lahu, Max Tsai, Frank Ogrinc, Avi Reichenberg, Steve C Williams, Mitul A Mehta, Sukhi S Shergill, James Gilleen, Yakub Farah, Cate Davison, Sarah Kerins, Lorena Valdearenas, Tolga Uz, Gez Lahu, Max Tsai, Frank Ogrinc, Avi Reichenberg, Steve C Williams, Mitul A Mehta, Sukhi S Shergill

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’.

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

References

    1. Bach ME, Barad M, Son H, Zhuo M, Lu YF, Shih R, Mansuy I, Hawkins RD, Kandel ER. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci U S A. 1999;96:5280–5285.
    1. Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci U S A. 1998;95:15020–15025.
    1. Blokland A, Menniti FS, Prickaerts J. PDE inhibition and cognition enhancement. Expert Opin Ther Pat. 2012;22:349–354.
    1. Bourtchouladze R, Lidge R, Catapano R, Stanley J, Gossweiler S, Romashko D, Scott R, Tully T. A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase. Proc Natl Acad Sci U S A. 2003;100:10518–10522.
    1. Bowie CR, Reichenberg A, Patterson TL, Heaton RK, Harvey PD. Determinants of real-world functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and symptoms. Am J Psychiatry. 2006;163(3):418–425.
    1. Brandt J, Benedict RHB. The Hopkins verbal learning test—revised: professional manual. Odessa: Psychological Assessment Resources, Inc.; 2001.
    1. Conti M, Jin SLC. The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res. 1999;63:1–38.
    1. Cooper DMF. Regulation and organization of adenylyl cyclases and cAMP. Biochem J. 2003;375:517–529.
    1. Curtis CE, D’Esposito M. Persistent activity in the prefrontal cortex during working memory. Trends Cogn Sci. 2003;7:415–423.
    1. Davis JA, Gould TJ. Rolipram attenuates MK-801-induced deficits in latent inhibition. Behav Neurosci. 2005;119:595–602.
    1. Egawa T, Mishima K, Matsumoto Y, Iwasaki K, Iwasaki K, Fujiwara M. Rolipram and its optical isomers, phosphodiesterase 4 inhibitors, attenuated the scopolamine-induced impairments of learning and memory in rats. Jpn J Pharmacol. 1997;75:275–281.
    1. Fertig BA, Baillie GS. PDE4-mediated cAMP signalling. J Cardiovasc Dev Dis. 2018;5(1):8.
    1. Gilleen J. Cognitive enhancement in schizophrenia. In: Keefe RSE, Reichenberg A, Cummings J, editors. Cognitive enhancement in CNS disorders and beyond. NY: Oxford University Press; 2017. pp. 177–212.
    1. Gilleen J, Michalopoulou PG, Reichenberg A, Drake R, Wykes T, Lewis SW, Kapur S. Modafinil combined with cognitive training is associated with improved learning in healthy volunteers–a randomised controlled trial. Eur Neuropsychopharmacol. 2014;24:529–539.
    1. Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology. 2004;174(1):3–16.
    1. Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia : implications for MATRICS. Schizophr Res. 2004;72:41–51.
    1. Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998;12:426–445.
    1. Hosseini-Sharifabad A, Ghahremani MH, Sabzevari O, Naghdi N, Abdollahi M, Beyer C, Bollen E, Prickaerts J, Roghani A, Sharifzadeh M. Effects of protein kinase A and G inhibitors on hippocampal cholinergic markers expressions in rolipram- and sildenafil-induced spatial memory improvement. Pharmacol Biochem Behav. 2012;101:311–319.
    1. Imanishi T, Sawa A, Ichimaru Y, Miyashiro M, Kato S, Yamamoto T, Ueki S. Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents. Eur J Pharmacol. 1997;321:273–278.
    1. Jabaris SGSL, Sumathy H, Kumar RS, Narayanan S, Thanikachalam S, Babu CS. Effects of rolipram and roflumilast, phosphodiesterase-4 inhibitors, on hypertension-induced defects in memory function in rats. Eur J Pharmacol. 2015;746:138–147.
    1. Johnson SC, Saykin AJ, Flashman LA, McAllister TW, Sparling MB. Brain activation on fMRI and verbal memory ability: functional neuroanatomic correlates of CVLT performance. J Int Neuropsychol Soc. 2001;7:55–62.
    1. Kay SR, Flszbein A, Opfer LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bull. 1987;13:261–276.
    1. Kuroiwa M, Snyder GL, Shuto T, Fukuda A, Yanagawa Y, Benavides DR, Nairn AC, Bibb JA, Greengard P, Nishi A. Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. Psychopharmacology. 2012;219:1065–1079.
    1. Marquand AF, De Simoni S, Moura J, Mehta MA. Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers. Neuropsychopharmacol. 2011;36(6):1237–1247.
    1. Mehta MA, Owen AM, Sahakian BJ, Mavaddat N, Pickard JD, Robbins TW. Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain. J Neurosci. 2000;20:65.
    1. Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al. The MATRICS consensus cognitive battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008;165:203–213.
    1. O’Carroll R. Cognitive impairment in schizophrenia. Adv Psychiatr Treat. 2000;6(3):161–168.
    1. Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa T, Sudo Y, Matsushima E, Iyo M, Tateno Y, Toru M. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature. 1997;385:634–636.
    1. Peng S, Sun H, Zhang X, Liu G, Wang G. Effects of selective phosphodiesterases-4 inhibitors on learning and memory: a review of recent research. Cell Biochem Biophys. 2014;70:83–85.
    1. Pérez-Torres S, Miró X, Palacios JM, Cortés R, Puigdoménech P, Mengod G. Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and [3 H] rolipram binding autoradiography: comparison with monkey and rat brain. J Chem Neuroanat. 2000;20:349–374.
    1. Rodefer JS, Saland SK, Eckrich SJ. Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats. Neuropharmacology. 2012;62:1182–1190.
    1. Rutten K, Prickaerts J, Blokland A. Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action. Neurobiol Learn Mem. 2006;85:132–138.
    1. Rutten K, Basile JL, Prickaerts J, Blokland A, Vivian JA. Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques. Psychopharmacology. 2008;196:643–648.
    1. Rutten K, Van Donkelaar EL, Ferrington L, Blokland A, Bollen E, Steinbusch HW, et al. Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats. Neuropsychopharmacol. 2009;34:1914–1925.
    1. Taylor JR, Birnbaum S, Ubriani R, Arnsten AF. Activation of cAMP-dependent protein kinase A in prefrontal cortex impairs working memory performance. J Neurosci. 1999;19(18):RC23–RC23.
    1. Van der Aart J, Salinas C, Dimber R, Pampols-Maso S, Weekes AA, Tonkyn J, et al. (2017) Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study. J Cerebr Blood Flow Metab 0(0): 1–8
    1. Van Duinen M, AO Reneerkens, Lambrecht L, Sambeth A, Rutten BP, Van Os J, et al. (2015) Treatment of cognitive impairment in schizophrenia: potential value of phosphodiesterase inhibitors in prefrontal dysfunction. Curr Pharm Des 21: 3813–3828
    1. Van Duinen M, Heckman PRA, Vanmierlo T, Sambeth A, Ogrinc F, Tsai M, Lahu G, Uz T, Blokland A, Prickaerts J. The PDE4-inhbitor roflumilast improves episodic memory: findings from a translational perspective. Eur Neuropsychopharmacol. 2017;27:S1024–S1025.
    1. Van Duinen MA, Sambeth A, Heckman PR, Smit S, Tsai M, Lahu G, Uz T, Blokland A, Prickaerts J. Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults. Neuropharmacology. 2018;131:31–38.
    1. Vanmierlo T, Creemers P, Akkerman S, van Duinen M, Sambeth A, De Vry J, et al. The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses. Behav Brain Res. 2016;303:26–33.
    1. Wallace TL, Ballard TM, Pouzet B, Riedel WJ, Wettstein JG. Pharmacology, biochemistry and behavior drug targets for cognitive enhancement in neuropsychiatric disorders. Pharmacol Biochem Behav. 2011;99:130–145.
    1. Wechsler D. Wechsler memory scale - Third Edition. San Antonio: The Psychological Corporation; 1997.
    1. Zhang HT, O’Donnell JM. Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats. Psychopharmacology. 2000;150:311–316.
    1. Zhang HT, Crissman AM, Dorairaj NR, Chandler LJ, O’Donnell JM. Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology. 2000;23:198–204.

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