Cognitive impairments are prevalent in schizophrenia and are associated with functional outcomes, yet there are currently no approved treatments to address these deficits. Roflumilast, a phosphodiesterase 4 inhibitor, has previously been shown to improve verbal memory in healthy and schizophrenia populations.
Aims:
This study aimed to investigate the neural changes which occur with roflumilast administration and which may underpin these cognitive effects.
Methods:
Ten participants with schizophrenia were administered 8 days of placebo, 100 and 250 µg of roflumilast in a 3-way crossover design. We present analyses of seed-based functional connectivity (FC) with bilateral hippocampus (HC) and regional cerebral blood flow measured with arterial spin labelling.
Results:
Results indicated that 250 µg roflumilast was associated with significantly greater FC between HC and prefrontal cortex (PFC) compared to placebo. There was also a significant increase in cerebral blood flow with 250 µg roflumilast relative to placebo in the dorsolateral PFC and HC.
Conclusions:
These changes provide preliminary support for a cerebral mechanism of action of roflumilast, which includes modulation of brain regions involved in memory known to be impaired in patients with schizophrenia. This data supports existing findings suggesting roflumilast has the potential to be an effective treatment for cognitive impairments in schizophrenia.
AchimAMLepageM (2005) Neural correlates of memory for items and for associations: An event-related functional magnetic resonance imaging study. Journal of Cognitive Neuroscience17(4): 652–667.
2.
AlexanderMPStussDTFansabedianN (2003) California verbal learning test: Performance by patients with focal frontal and non-frontal lesions. Brain: A Journal of Neurology126(Pt 6): 1493–1503.
3.
AndreasenNCRezaiKAlligerR, et al. (1992) Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Archives of General Psychiatry49(12): 943–958.
4.
AhnaouABroadbeltTBiermansR, et al. (2020) The phosphodiesterase-4 and glycine transporter-1 inhibitors enhance in vivo hippocampal theta network connectivity and synaptic plasticity, whereas D-serine does not. Translational Psychiatry10(1): 197.
5.
AntoniadesMSchoelerTRaduaJ, et al. (2018) Verbal learning and hippocampal dysfunction in schizophrenia: A meta-analysis. Neuroscience and Biobehavioral Reviews86: 166–175.
6.
AshburnerJ (2007) A fast diffeomorphic image registration algorithm. NeuroImage38(1): 95–113.
7.
AxmacherNSchmitzDPWagnerT, et al. (2008) Interactions between medial temporal lobe, prefrontal cortex, and inferior temporal regions during visual working memory: A combined intracranial EEG and functional magnetic resonance imaging study. Journal of Neuroscience28(29): 7304–7312.
8.
BähnerFMeyer-LindenbergA (2017) Hippocampal–prefrontal connectivity as a translational phenotype for schizophrenia. European Neuropsychopharmacology27(2): 93–106.
9.
BaradMBourtchouladzeRWinderDG, et al. (1998) Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proceedings of the National Academy of Sciences of the United States of America95(25): 15020–15025.
10.
BloklandAVan DuinenMASambethA, et al. (2019) Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: A double-blind placebo-controlled study. Neurobiology of Aging77: 37–43.
11.
Bonner-JacksonAHautKCsernanskyJG, et al. (2005) The influence of encoding strategy on episodic memory and cortical activity in schizophrenia. Biological Psychiatry58(1): 47–55.
12.
BowieCRHarveyPD (2006) Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatric Disease and Treatment2(4): 531–536.
13.
BrettMAntonJLValabregueR, et al. (2002) Region of interest analysis using an SPM toolbox [abstract]. In: Presented at the 8th International Conference on Functional Mapping of the Human Brain, Sendai, Japan. Available on CD-ROM in NeuroImage, Vol 16, No 2.
14.
CarterCSPerlsteinWGanguliR, et al. (1998) Functional hypofrontality and working memory dysfunction in schizophrenia. The American Journal of Psychiatry155(9): 1285–1287.
15.
CastnerSAGoldman-RakicPSWilliamsGV (2004) Animal models of working memory: Insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology174(1): 111–125.
16.
ChengY-FWangCLinH-B, et al. (2010) Inhibition of phosphodiesterase-4 reverses memory deficits produced by Aβ25-35 or Aβ1-40 peptide in rats. Psychopharmacology212(2): 181–191.
17.
CohenMX (2011) Hippocampal-prefrontal connectivity predicts midfrontal oscillations and long-term memory performance. Current Biology21(22): 1900–1905.
18.
ColginLL (2011) Oscillations and hippocampal-prefrontal synchrony. Current Opinion in Neurobiology21(3): 467–474.
19.
CousijnHTunbridgeEMRolinskiM, et al. (2015) Modulation of hippocampal theta and hippocampal-prefrontal cortex function by a schizophrenia risk gene. Human Brain Mapping36(6): 2387–2395.
20.
CuiL-BLiuJWangL-X, et al. (2015) Anterior cingulate cortex-related connectivity in first-episode schizophrenia: A spectral dynamic causal modeling study with functional magnetic resonance imaging. Frontiers in Human Neuroscience9: 589.
21.
DaiWGarciaDDe BazelaireC, et al. (2008) Continuous flow-driven inversion for arterial spin labeling using pulsed radio frequency and gradient fields. Magnetic Resonance in Medicine60(6): 1488–1497.
22.
DanionJ-MHuronCVidailhetP, et al. (2007) Functional mechanisms of episodic memory impairment in schizophrenia. Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie52(11): 693–701.
23.
DugréJRDumaisATikaszA, et al. (2021) Functional connectivity abnormalities of the long-axis hippocampal subregions in schizophrenia during episodic memory. NPJ Schizophrenia7(1): 19.
24.
DuinenMVReneerkensOAHLambrechtL, et al. (2015) Treatment of cognitive impairment in schizophrenia: Potential value of phosphodiesterase inhibitors in prefrontal dysfunction. Current Pharmaceutical Design21(26): 3813–3828.
ElmerSBurkardMRenzB, et al. (2009) Direct current induced short-term modulation of the left dorsolateral prefrontal cortex while learning auditory presented nouns. Behavioral and Brain Functions: BBF5: 29.
27.
FletcherPCStephensonCMECarpenterTA, et al. (2003) Regional brain activations predicting subsequent memory success: An event-related fMRI study of the influence of encoding tasks. Cortex39(4): 1009–1026.
28.
GilleenJFarahYDavisonC, et al. (2021a) An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients. Psychopharmacology238(5): 1279–1289.
29.
GilleenJNottageJYakubF, et al. (2021b) The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial. Journal of Psychopharmacology (Oxford, England)35(1): 15–22.
30.
GoldbergTEBermanKFMohrE, et al. (1990) Regional cerebral blood flow and cognitive function in Huntington’s disease and schizophrenia. A comparison of patients matched for performance on a prefrontal-type task. Archives of Neurology47(4): 418–422.
31.
GuoJYRaglandJDCarterCS (2019) Memory and cognition in schizophrenia. Molecular Psychiatry24(5): 633–642.
32.
Hosseini-SharifabadAGhahremaniMHSabzevariO, et al. (2012) Effects of protein kinase A and G inhibitors on hippocampal cholinergic markers expressions in rolipram- and sildenafil-induced spatial memory improvement. Pharmacology, Biochemistry, and Behavior101(3): 311–319.
33.
InnocentiIGiovannelliFCincottaM, et al. (2010) Event-related rTMS at encoding affects differently deep and shallow memory traces. NeuroImage53(1): 325–330.
34.
JenkinsonMBeckmannCFBehrensTEJ, et al. (2012) FSL. NeuroImage62(2): 782–790.
35.
KaySRFiszbeinAOplerLA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin13(2): 261–276.
36.
KircherTWeisSLeubeD, et al. (2008) Anterior hippocampus orchestrates successful encoding and retrieval of non-relational memory: An event-related fMRI study. European Archives of Psychiatry and Clinical Neuroscience258(6): 363–372.
37.
KraguljacNVSrivastavaALahtiAC (2013) Memory deficits in schizophrenia: A selective review of functional magnetic resonance imaging (fMRI) studies. Behavioral Sciences3(3): 330–347.
38.
KuroiwaMSnyderGLShutoT, et al. (2012) Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. Psychopharmacology219(4): 1065–1079.
39.
LakicsVKarranEHBoessFG (2010) Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology59(6): 367–374.
40.
LepageMMontoyaAPelletierM, et al. (2006) Associative memory encoding and recognition in schizophrenia: An event-related fMRI study. Biological Psychiatry60(11): 1215–1223.
41.
LiangMZhouYJiangT, et al. (2006) Widespread functional disconnectivity in schizophrenia with resting-state functional magnetic resonance imaging. Neuroreport17(2): 209–213.
42.
LiebermanJAGirgisRRBrucatoG, et al. (2018) Hippocampal dysfunction in the pathophysiology of schizophrenia: A selective review and hypothesis for early detection and intervention. Molecular Psychiatry23(8): 1764–1772.
43.
LivingstonNRHawkinsPCGilleenJ, et al. (2021) Preliminary evidence for the phosphodiesterase type-4 inhibitor, roflumilast, in ameliorating cognitive flexibility deficits in patients with schizophrenia. Journal of Psychopharmacology (Oxford, England)35(9): 1099–1110.
44.
Mesholam-GatelyRIGiulianoAJGoffKP, et al. (2009) Neurocognition in first-episode schizophrenia: A meta-analytic review. Neuropsychology23(3): 315–336.
45.
Nieto-CastanonA (2020) Handbook of Functional Connectivity Magnetic Resonance Imaging Methods in CONN. Hilbert Press.
46.
OttenLJHensonRNRuggMD (2001) Depth of processing effects on neural correlates of memory encoding: Relationship between findings from across- and within-task comparisons. Brain: A Journal of Neurology124(Pt 2): 399–412.
47.
PallerKAWagnerAD (2002) Observing the transformation of experience into memory. Trends in Cognitive Sciences6(2): 93–102.
48.
PangLKennedyDWeiQ, et al. (2017) Decreased functional connectivity of insular cortex in drug naïve first episode schizophrenia: In relation to symptom severity. PLoS One12(1): e0167242.
49.
RaglandJDGurRCValdezJN, et al. (2005) Levels-of-processing effect on frontotemporal function in schizophrenia during word encoding and recognition. The American Journal of Psychiatry162(10): 1840–1848.
50.
RaglandJDLairdARRanganathC, et al. (2009) Prefrontal activation deficits during episodic memory in schizophrenia. The American Journal of Psychiatry166(8): 863–874.
51.
RiedlVUtzLCastrillónG, et al. (2016) Metabolic connectivity mapping reveals effective connectivity in the resting human brain. Proceedings of the National Academy of Sciences113(2): 428–433.
52.
RossiSCappaSFBabiloniC, et al. (2001) Prefontal cortex in long-term memory: An “interference” approach using magnetic stimulation. Nature Neuroscience4(9): 948–952.
53.
RuttenKBasileJLPrickaertsJ, et al. (2008) Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques. Psychopharmacology196(4): 643–648.
54.
SamudraNIvlevaEIHubbardNA, et al. (2015) Alterations in hippocampal connectivity across the psychosis dimension. Psychiatry Research233(2): 148–157.
55.
Sans-SansaBMcKennaPJCanales-RodríguezEJ, et al. (2013) Association of formal thought disorder in schizophrenia with structural brain abnormalities in language-related cortical regions. Schizophrenia Research146(1–3): 308–313.
56.
SimonsJSSpiersHJ (2003) Prefrontal and medial temporal lobe interactions in long-term memory. Nature Reviews. Neuroscience4(8): 637–648.
57.
SuazoVDíezÁTamayoP, et al. (2013) Limbic hyperactivity associated to verbal memory deficit in schizophrenia. Journal of Psychiatric Research47(6): 843–850.
58.
TianYZaleskyABousmanC, et al. (2019) Insula functional connectivity in schizophrenia: Subregions, gradients, and symptoms. Biological Psychiatry. Cognitive Neuroscience and Neuroimaging4(4): 399–408.
59.
UhlhaasPJHaenschelCNikolićD, et al. (2008) The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. Schizophrenia Bulletin34(5): 927–943.
60.
Van Der AartJSalinasCDimberR, et al. (2018) Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study. Journal of Cerebral Blood Flow & Metabolism38(11): 2033–2040.
61.
Van DuinenMASambethAHeckmanPRA, et al. (2018) Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults. Neuropharmacology131: 31–38.
62.
WangZ-ZYangW-XZhangY, et al. (2015) Phosphodiesterase-4D knock-down in the prefrontal cortex alleviates chronic unpredictable stress-induced depressive-like behaviors and memory deficits in mice. Scientific Reports5: 11332.
63.
WeinbergerDRBermanKFZecRF (1986) Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Archives of General Psychiatry43(2): 114–124.
64.
WhiteJABanksMIPearceRA, et al. (2000) Networks of interneurons with fast and slow gamma-aminobutyric acid type A (GABAA) kinetics provide substrate for mixed gamma-theta rhythm. Proceedings of the National Academy of Sciences of the United States of America97(14): 8128–8133.
65.
Whitfield-GabrieliSNieto-CastanonA (2012) Conn: A functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connectivity2(3): 125–141.
66.
WiescholleckVManahan-VaughanD (2012) PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis. Translational Psychiatry2(3): e89.
67.
WolfDHGurRCValdezJN, et al. (2007) Alterations of fronto-temporal connectivity during word encoding in schizophrenia. Psychiatry research154(3): 221–232.
68.
XuYZhangHTO’DonnellJM (2011) Phosphodiesterases in the central nervous system: Implications in mood and cognitive disorders. Handbook of Experimental Pharmacology204: 447–485.
69.
ZhouYLiangMTianL, et al. (2007) Functional disintegration in paranoid schizophrenia using resting-state fMRI. Schizophrenia Research97(1–3): 194–205.
70.
ZhouYShuNLiuY, et al. (2008) Altered resting-state functional connectivity and anatomical connectivity of hippocampus in schizophrenia. Schizophrenia Research100(1–3): 120–132.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
