Abstract
Several lines of evidence have implicated white matter (WM) deficits in schizophrenia, including microstructural alterations from diffusion tensor (DTI) brain imaging studies. It has been proposed that dysregulated inflammatory processes, including heightened activity of circulating lymphocytes, may contribute to WM pathology in this illness. Fingolimod is a sphingosine-1-phosphate (S1P) receptor agonist that is approved for the treatment of relapsing multiple sclerosis (MS). Fingolimod robustly decreases the number of circulating lymphocytes through sequestration of these cells in lymph tissue. In addition, this agent improved WM microstructure as shown by increases in DTI fractional anisotropy (FA). In this pilot study, we assessed the effects of fingolimod on WM microstructure, cognition and symptoms in an eight-week, double-blind trial. Forty subjects with schizophrenia or schizoaffective disorder were randomized 1:1 to fingolimod (0.5 mg/day) and placebo. Fingolimod caused significant reductions in circulating lymphocytes (p < .001). In addition, there was a statistically non-significant association (p = .089) between DTI-FA change in the WM skeleton and fingolimod. There were significant relationships between the degree of lymphocyte reductions and increases in FA in the corpus collosum (p = .004) and right superior longitudinal fasciculus ( p = .02), and a non-significant correlation with the WM skeleton. There were no significant fingolimod versus placebo interactions on cognitive or symptom measures. There were no serious adverse events related to fingolimod treatment. Future studies with larger samples and treatment durations are needed to further establish fingolimod’s potential therapeutic effects in schizophrenia.
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References
Banks, W. A. (2005). Blood-brain bytokines: a mechanism for neuropathology. Current Pharmaceutical Design, 11(8), 973–984. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15777248.
Barch, D. M., & Ceaser, A. (2012). Cognition in schizophrenia: core psychological and neural mechanisms. Trends in Cognitive Sciences, 16(1), 27–34. https://doi.org/10.1016/j.tics.2011.11.015
Berger, G. E., Proffitt, T. M., McConchie, M., Yuen, H., Wood, S. J., Amminger, G. P., & McGorry, P. D. (2007). Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. The Journal of Clinical Psychiatry, 68(12), 1867–1875. https://doi.org/10.4088/jcp.v68n1206
Berk, M., Copolov, D., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., & Bush, A. I. (2008). N-acetyl cysteine as a glutathione precursor for schizophrenia–a double-blind, randomized, placebo-controlled trial. Biological Psychiatry, 64(5), 361–368. https://doi.org/10.1016/j.biopsych.2008.03.004
Beumer, W., Drexhage, R. C., De Wit, H., Versnel, M. A., Drexhage, H. A., & Cohen, D. (2012a). Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome. Psychoneuroendocrinology, 37(12), 1901–1911. https://doi.org/10.1016/j.psyneuen.2012.04.001.
Beumer, W., Gibney, S. M., Drexhage, R. C., Pont-Lezica, L., Doorduin, J., Klein, H. C., & Drexhage, H. A. (2012b). The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. Journal of Leukocyte Biology, 92(5), 959–975. https://doi.org/10.1189/jlb.0212100
Birur, B., Kraguljac, N. V., Shelton, R. C., & Lahti, A. C. (2017). Brain structure, function, and neurochemistry in schizophrenia and bipolar disorder-a systematic review of the magnetic resonance neuroimaging literature. NPJ Schizophrenia, 3, 15. https://doi.org/10.1038/s41537-017-0013-9
Branzoli, F., Ercan, E., Valabregue, R., Wood, E. T., Buijs, M., Webb, A., & Ronen, I. (2016). Differentiating between axonal damage and demyelination in healthy aging by combining diffusion-tensor imaging and diffusion-weighted spectroscopy in the human corpus callosum at 7 T. Neurobiology of Aging, 47, 210–217. https://doi.org/10.1016/j.neurobiolaging.2016.07.022
Breier, A., Liffick, E., Hummer, T. A., Vohs, J. L., Yang, Z., Mehdiyoun, N. F., & Francis, M. M. (2018). Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophrenia Research, 199, 395–402. https://doi.org/10.1016/j.schres.2018.03.012
Bullmore, E. T., Frangou, S., & Murray, R. M. (1997). The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia. Schizophrenia Research, 28(2–3), 143–156. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9468349.
Busse, S., Busse, M., Schiltz, K., Bielau, H., Gos, T., Brisch, R., & Steiner, J. (2012). Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations? Brain, Behavior, and Immunity, 26(8), 1273–1279. https://doi.org/10.1016/j.bbi.2012.08.005
Cai, H. Q., Catts, V. S., Webster, M. J., Galletly, C., Liu, D., O’Donnell, M., & Weickert, C. S. (2020). Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation. Molecular Psychiatry, 25(4), 761–775. https://doi.org/10.1038/s41380-018-0235-x
Cakici, N., Sutterland, A. L., Penninx, B., Dalm, V. A., de Haan, L., & van Beveren, N. J. M. (2020). Altered peripheral blood compounds in drug-naive first-episode patients with either schizophrenia or major depressive disorder: a meta-analysis. Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2020.04.039
Cakici, N., van Beveren, N. J. M., Judge-Hundal, G., Koola, M. M., & Sommer, I. E. C. (2019). An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis. Psychological Medicine, 49(14), 2307–2319. https://doi.org/10.1017/S0033291719001995
Capuzzi, E., Bartoli, F., Crocamo, C., Clerici, M., & Carra, G. (2017). Acute variations of cytokine levels after antipsychotic treatment in drug-naive subjects with a first-episode psychosis: A meta-analysis. Neuroscience & Biobehavioral Reviews, 77, 122–128. https://doi.org/10.1016/j.neubiorev.2017.03.003
Chen, H., Wu, J., Zhang, J., Fuita, Y., Ishima, T., Iyo, M., & Hashinoto, K. (2012). Protective effects of the antioxidant sulforaphane on behavioral changes and neurotoxicity in mice after the administration of methamphetamine. Psychopharmacology (222), 37–45.
Chun, J., & Hartung, H. P. (2010). Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clinical Neuropharmacology, 33(2), 91–101. https://doi.org/10.1097/WNF.0b013e3181cbf825
Coelho, R. P., Payne, S. G., Bittman, R., Spiegel, S., & Sato-Bigbee, C. (2007). The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. Journal of Pharmacology and Experimental Therapeutics, 323(2), 626–635. https://doi.org/10.1124/jpet.107.123927
Cohen, J. A., Barkhof, F., Comi, G., Hartung, H. P., Khatri, B. O., Montalban, X., & Group, T. S. (2010). Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. The New England Journal of Medicine, 362(5), 402–415. https://doi.org/10.1056/NEJMoa0907839
Davis, K. L., Stewart, D. G., Friedman, J. I., Buchsbaum, M., Harvey, P. D., Hof, P. R., & Haroutunian, V. (2003). White matter changes in schizophrenia: evidence for myelin-related dysfunction. Archives Of General Psychiatry, 60(5), 443–456. https://doi.org/10.1001/archpsyc.60.5.443
Emsley, R., Chiliza, B., Asmal, L., du Plessis, S., Phahladira, L., van Niekerk, E., & Harvey, B. H. (2014). A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia. Schizophrenia Research, 158(1–3), 230–235. https://doi.org/10.1016/j.schres.2014.06.004
Emsley, R., Myburgh, C., Oosthuizen, P., & van Rensburg, S. J. (2002). Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. The American Journal of Psychiatry, 159(9), 1596–1598. https://doi.org/10.1176/appi.ajp.159.9.1596
Fan, Q., Tian, Q., Ohringer, N. A., Nummenmaa, A., Witzel, T., Tobyne, S. M., & Huang, S. Y. (2019). Age-related alterations in axonal microstructure in the corpus callosum measured by high-gradient diffusion MRI. Neuroimage, 191, 325–336. https://doi.org/10.1016/j.neuroimage.2019.02.036
Farokhnia, M., Azarkolah, A., Adinehfar, F., Khodaie-Ardakani, M. R., Hosseini, S. M., Yekehtaz, H., & Akhondzadeh, S. (2013). N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clinical Neuropharmacology, 36(6), 185–192. https://doi.org/10.1097/WNF.0000000000000001
Fenton, W. S., Dickerson, F., Boronow, J., Hibbeln, J. R., & Knable, M. (2001). A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. The American Journal of Psychiatry, 158(12), 2071–2074. https://doi.org/10.1176/appi.ajp.158.12.2071
First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. B. W. (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version Patient Edition. New York: New York State Psychiatric Institute.
Fond, G., Hamdani, N., Kapczinski, F., Boukouaci, W., Drancourt, N., Dargel, A., & Leboyer, M. (2014). Effectiveness and tolerance of anti-inflammatory drugs’ add-on therapy in major mental disorders: a systematic qualitative review. Acta Psychiatrica Scandinavica, 129(3), 163–179. https://doi.org/10.1111/acps.12211
Foster, C. A., Howard, L. M., Schweitzer, A., Persohn, E., Hiestand, P. C., Balatoni, B., & Billich, A. (2007). Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. Journal of Pharmacology and Experimental Therapeutics, 323(2), 469–475. https://doi.org/10.1124/jpet.107.127183
Galderisi, S., Davidson, M., Kahn, R. S., Mucci, A., Boter, H., Gheorghe, M. D., & Group, E. (2009). Correlates of cognitive impairment in first episode schizophrenia: the EUFEST study. Schizophrenia Research, 115(2–3), 104–114. https://doi.org/10.1016/j.schres.2009.09.022
Garcia-Bueno, B., Bioque, M., Mac-Dowell, K. S., Barcones, M. F., Martinez-Cengotitabengoa, M., Pina-Camacho, L., & Leza, J. C. (2014). Pro-/anti-inflammatory dysregulation in patients with first episode of psychosis: toward an integrative inflammatory hypothesis of schizophrenia. Schizophrenia Bulletin, 40(2), 376–387. https://doi.org/10.1093/schbul/sbt001
Gehrmann, J., Matsumoto, Y., & Kreutzberg, G. W. (1995). Microglia: intrinsic immuneffector cell of the brain. Brain Research Reviews, 20(3), 269–287. https://doi.org/10.1016/0165-0173(94)00015-h
Gurevich, M., Waknin, R., Stone, E., & Achiron, A. (2018). Fingolimod-improved axonal and myelin integrity of white matter tracts associated with multiple sclerosis-related functional impairments. CNS Neuroscience & Therapeutics, 24(5), 412–419. https://doi.org/10.1111/cns.12796
Guy, W. (1976a). ECDEU assessment manual for psychopharacology, revised. In: National Institute of Mental Health. Psychopharmacology Research Branch (pp. 217–331). Rockville, MD.
Guy, W. (1976b). ECDEU assessment manual for psychopharmacology, revised. Retrieved from Rockville, MD.
Hafizi, S., Tseng, H. H., Rao, N., Selvanathan, T., Kenk, M., Bazinet, R. P., & Mizrahi, R. (2017). Imaging microglial activation in untreated first-episode psychosis: A PET study with [(18)F]FEPPA. The American Journal of Psychiatry, 174(2), 118–124. https://doi.org/10.1176/appi.ajp.2016.16020171
Haijma, S. V., Van Haren, N., Cahn, W., Koolschijn, P. C., Pol, H., & Kahn, R. S. (2013). Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophrenia Bulletin, 39(5), 1129–1138. https://doi.org/10.1093/schbul/sbs118
Harvey, P. D., Bowie, C. R., & Friedman, J. I. (2001). Cognition in schizophrenia. Current Psychiatry Reports, 3(5), 423–428. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11559481.
Hof, P. R., Haroutunian, V., Friedrich, V. L. Jr., Byne, W., Buitron, C., Perl, D. P., & Davis, K. L. (2003). Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biological Psychiatry, 53(12), 1075–1085. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12814859.
Hosoi, T., Okuma, Y., & Nomura, Y. (2002). The mechanisms of immune-to-brain communication in inflammation as a drug target. Current Drug Targets - Inflammation & Allergy, 1(3), 257–262. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14561190.
Hu, X., Zhou, H., Zhang, D., Yang, S., Qian, L., Wu, H. M., & Hong, J. S. (2012). Clozapine protects dopaminergic neurons from inflammation-induced damage by inhibiting microglial overactivation. Journal of Neuroimmune Pharmacology, 7(1), 187–201. https://doi.org/10.1007/s11481-011-9309-0
Huang, S. Y., Nummenmaa, A., Witzel, T., Duval, T., Cohen-Adad, J., Wald, L. L., & McNab, J. A. (2015). The impact of gradient strength on in vivo diffusion MRI estimates of axon diameter. Neuroimage, 106, 464–472. https://doi.org/10.1016/j.neuroimage.2014.12.008
Hummer, T. A., Francis, M. M., Vohs, J. L., Liffick, E., Mehdiyoun, N. F., & Breier, A. (2018). Characterization of white matter abnormalities in early-stage schizophrenia. Early Intervention in Psychiatry, 12(4), 660–668. https://doi.org/10.1111/eip.12359
Jones, D. K., Knosche, T. R., & Turner, R. (2013). White matter integrity, fiber count, and other fallacies: the do’s and don’ts of diffusion MRI. Neuroimage, 73, 239–254. https://doi.org/10.1016/j.neuroimage.2012.06.081
Jung, C. G., Kim, H. J., Miron, V. E., Cook, S., Kennedy, T. E., Foster, C. A., & Soliven, B. (2007). Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia, 55(16), 1656–1667. https://doi.org/10.1002/glia.20576
Kappos, L., Antel, J., Comi, G., Montalban, X., O’Connor, P., Polman, C. H., & Group, F. D. S. (2006). Oral fingolimod (FTY720) for relapsing multiple sclerosis. The New England Journal of Medicine, 355(11), 1124–1140. https://doi.org/10.1056/NEJMoa052643
Kappos, L., Radue, E. W., Chin, P., Ritter, S., Tomic, D., & Lublin, F. (2016). Onset of clinical and MRI efficacy occurs early after fingolimod treatment initiation in relapsing multiple sclerosis. Journal of Neurology, 263(2), 354–360. https://doi.org/10.1007/s00415-015-7978-y
Kappos, L., Radue, E. W., O’Connor, P., Polman, C., Hohlfeld, R., Calabresi, P., & Group, F. S. (2010). A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. The New England Journal of Medicine, 362(5), 387–401. https://doi.org/10.1056/NEJMoa0909494
Karlsgodt, K. H. (2016). Diffusion imaging of white matter in schizophrenia: Progress and future directions. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 1(3), 209–217. https://doi.org/10.1016/j.bpsc.2015.12.001
Kay, S. R., Fiszbein, A., & Opler, L. A. (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13(2), 261–276. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/3616518.
Kealy, J., Greene, C., & Campbell, M. (2018). Blood-brain barrier regulation in psychiatric disorders. Neuroscience Letters. https://doi.org/10.1016/j.neulet.2018.06.033
Keefe, R. S., Goldberg, T. E., Harvey, P. D., Gold, J. M., Poe, M. P., & Coughenour, L. (2004). The brief assessment of cognition in schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophrenia Research, 68(2–3), 283–297. https://doi.org/10.1016/j.schres.2003.09.011
Kelly, S., Jahanshad, N., Zalesky, A., Kochunov, P., Agartz, I., Alloza, C., & Donohoe, G. (2018). Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group. Molecular Psychiatry, 23(5), 1261–1269. https://doi.org/10.1038/mp.2017.170
Kirkpatrick, B., & Miller, B. J. (2013). Inflammation and schizophrenia. Schizophrenia Bulletin, 39(6), 1174–1179. https://doi.org/10.1093/schbul/sbt141
Kochunov, P., & Hong, L. E. (2014). Neurodevelopmental and neurodegenerative models of schizophrenia: white matter at the center stage. Schizophrenia Bulletin, 40(4), 721–728. https://doi.org/10.1093/schbul/sbu070
Kreutzberg, G. W. (1995). Microglia, the first line of defence in brain pathologies. Arzneimittelforschung, 45(3A), 357–360. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/7763326.
Kronfol, Z., & Remick, D. G. (2000). Cytokines and the brain: implications for clinical psychiatry. The American Journal of Psychiatry, 157(5), 683–694. https://doi.org/10.1176/appi.ajp.157.5.683
Kubicki, M., McCarley, R., Westin, C. F., Park, H. J., Maier, S., Kikinis, R., & Shenton, M. E. (2007). A review of diffusion tensor imaging studies in schizophrenia. Journal of Psychiatric Research, 41(1–2), 15–30. https://doi.org/10.1016/j.jpsychires.2005.05.005
Laskaris, L. E., Biase, D., Everall, M. A., Chana, I., Christopoulos, G., Skafidas, A., & Pantelis, E. (2016). Microglial activation and progressive brain changes in schizophrenia. British Journal of Pharmacology, 173(4), 666–680. https://doi.org/10.1111/bph.13364
Levkovitz, Y., Mendlovich, S., Riwkes, S., Braw, Y., Levkovitch-Verbin, H., Gal, G., & Kron, S. (2010). A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. The Journal of Clinical Psychiatry, 71(2), 138–149. https://doi.org/10.4088/JCP.08m04666yel
Mandala, S., Hajdu, R., Bergstrom, J., Quackenbush, E., Xie, J., Milligan, J., & Rosen, H. (2002). Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science, 296(5566), 346–349. https://doi.org/10.1126/science.1070238
Manjon, J. V., Coupe, P., Concha, L., Buades, A., Collins, D. L., & Robles, M. (2013). Diffusion weighted image denoising using overcomplete local PCA. PLoS One, 8(9), e73021. https://doi.org/10.1371/journal.pone.0073021
Marder, S. R., Davis, J. M., & Chouinard, G. (1997). The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. The Journal of Clinical Psychiatry, 58(12), 538–546. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9448657.
Miller, B. J., Buckley, P., Seabolt, W., Mellor, A., & Kirkpatrick, B. (2011). Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biological Psychiatry, 70(7), 663–671. https://doi.org/10.1016/j.biopsych.2011.04.013
Miron, V. E., Jung, C. G., Kim, H. J., Kennedy, T. E., Soliven, B., & Antel, J. P. (2008). FTY720 modulates human oligodendrocyte progenitor process extension and survival. Annals of Neurology, 63(1), 61–71. https://doi.org/10.1002/ana.21227
Miron, V. E., Ludwin, S. K., Darlington, P. J., Jarjour, A. A., Soliven, B., Kennedy, T. E., & Antel, J. P. (2010). Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. The American Journal of Pathology, 176(6), 2682–2694. https://doi.org/10.2353/ajpath.2010.091234
Monji, A., Kato, T., & Kanba, S. (2009). Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry and Clinical Neurosciences, 63(3), 257–265. https://doi.org/10.1111/j.1440-1819.2009.01945.x
Muller, N., Weidinger, E., Leitner, B., & Schwarz, M. J. (2015). The role of inflammation in schizophrenia. Frontiers in Neuroscience, 9, 372. https://doi.org/10.3389/fnins.2015.00372
Najjar, S., & Pearlman, D. M. (2015). Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophrenia Research, 161(1), 102–112. https://doi.org/10.1016/j.schres.2014.04.041
Nascimento, M. M., Suliman, M. E., Silva, M., Chinaglia, T., Marchioro, J., Hayashi, S. Y., & Anderstam, B. (2010). Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study. Peritoneal Dialysis International, 30(3), 336–342. https://doi.org/10.3747/pdi.2009.00073
Nikkila, H. V., Muller, K., Ahokas, A., Rimon, R., & Andersson, L. C. (2001). Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia. Schizophrenia Research, 49(1–2), 99–105. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11343869.
Pasternak, O., Westin, C. F., Dahlben, B., Bouix, S., & Kubicki, M. (2015). The extent of diffusion MRI markers of neuroinflammation and white matter deterioration in chronic schizophrenia. Schizophrenia Research, 161(1), 113–118. https://doi.org/10.1016/j.schres.2014.07.031
Peet, M., Brind, J., Ramchand, C. N., Shah, S., & Vankar, G. K. (2001). Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophrenia Research, 49(3), 243–251. https://doi.org/10.1016/s0920-9964(00)00083-9
Peet, M., Horrobin, D. F., & Group, E. E. M. S. (2002). A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. Journal of Psychiatric Research, 36(1), 7–18. https://doi.org/10.1016/s0022-3956(01)00048-6
Pillinger, T., D’Ambrosio, E., McCutcheon, R., & Howes, O. D. (2019). Is psychosis a multisystem disorder? A meta-review of central nervous system, immune, cardiometabolic, and endocrine alterations in first-episode psychosis and perspective on potential models. Molecular Psychiatry, 24(6), 776–794. https://doi.org/10.1038/s41380-018-0058-9
Pollak, T. A., Drndarski, S., Stone, J. M., David, A. S., McGuire, P., & Abbott, N. J. (2018). The blood-brain barrier in psychosis. The Lancet Psychiatry, 5(1), 79–92. https://doi.org/10.1016/S2215-0366(17)30293-6
Potvin, S., Stip, E., Sepehry, A. A., Gendron, A., Bah, R., & Kouassi, E. (2008). Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biological Psychiatry, 63(8), 801–808. https://doi.org/10.1016/j.biopsych.2007.09.024
Reis Marques, T., Taylor, H., Chaddock, C., Dell’acqua, F., Handley, R., Reinders, A. A., & Dazzan, P. (2014). White matter integrity as a predictor of response to treatment in first episode psychosis. Brain, 137(Pt 1), 172–182. https://doi.org/10.1093/brain/awt310
Riedel, M., Spellmann, I., Schwarz, M. J., Strassnig, M., Sikorski, C., Moller, H. J., & Muller, N. (2007). Decreased T cellular immune response in schizophrenic patients. Journal of Psychiatric Research, 41(1–2), 3–7. https://doi.org/10.1016/j.jpsychires.2005.11.007
Rosenberger, G., Kubicki, M., Nestor, P. G., Connor, E., Bushell, G. B., Markant, D., & Shenton, M. E. (2008). Age-related deficits in fronto-temporal connections in schizophrenia: a diffusion tensor imaging study. Schizophrenia Research, 102(1–3), 181–188. https://doi.org/10.1016/j.schres.2008.04.019
Samartzis, L., Dima, D., Fusar-Poli, P., & Kyriakopoulos, M. (2014). White matter alterations in early stages of schizophrenia: a systematic review of diffusion tensor imaging studies. Journal of Neuroimaging, 24(2), 101–110. https://doi.org/10.1111/j.1552-6569.2012.00779.x
Senda, J., Watanabe, H., Endo, K., Yasui, K., Hawsegawa, Y., Yoneyama, N., & Sobue, G. (2016). Active brain changes after initiating fingolimod therapy in multiple sclerosis patients using individual voxel-based analyses for diffusion tensor imaging. Nagoya Journal of Medical Science, 78(4), 455–463. https://doi.org/10.18999/nagjms.78.4.455
Skaper, S. D., Facci, L., & Giusti, P. (2014). Neuroinflammation, microglia and mast cells in the pathophysiology of neurocognitive disorders: a review. CNS & Neurological Disorders - Drug Targets, 13(10), 1654–1666. https://doi.org/10.2174/1871527313666141130224206
Smith, S. M. (2002). Fast robust automated brain extraction. Human Brain Mapping, 17(3), 143–155. https://doi.org/10.1002/hbm.10062
Smith, S. M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T. E., Mackay, C. E., & Behrens, T. E. J. (2006). Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. Neuroimage, 31(4), 1487–1505. https://doi.org/10.1016/J.Neuroimage.2006.02.024
Smith, S. M., & Nichols, T. E. (2009). Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage, 44(1), 83–98. https://doi.org/10.1016/j.neuroimage.2008.03.061
Tajik-Esmaeeli, S., Moazen-Zadeh, E., Abbasi, N., Shariat, S. V., Rezaei, F., Salehi, B., & Akhondzadeh, S. (2017). Simvastatin adjunct therapy for negative symptoms of schizophrenia: a randomized double-blind placebo-controlled trial. International Clinical Psychopharmacology, 32(2), 87–94. https://doi.org/10.1097/YIC.0000000000000159
Teijaro, J. R., Walsh, K. B., Cahalan, S., Fremgen, D. M., Roberts, E., Scott, F., & Rosen, H. (2011). Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell, 146(6), 980–991. https://doi.org/10.1016/j.cell.2011.08.015
Thomas, K., Proschmann, U., & Ziemssen, T. (2017a). Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis. Expert Opinion on Pharmacotherapy, 18(15), 1649–1660. https://doi.org/10.1080/14656566.2017.1373093
Thomas, K., Sehr, T., Proschmann, U., Rodriguez-Leal, F. A., Haase, R., & Ziemssen, T. (2017b). Fingolimod additionally acts as immunomodulator focused on the innate immune system beyond its prominent effects on lymphocyte recirculation. Journal of Neuroinflammation, 14(1), 41. https://doi.org/10.1186/s12974-017-0817-6
Upthegrove, R., Manzanares-Teson, N., & Barnes, N. M. (2014). Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophrenia Research, 155(1–3), 101–108. https://doi.org/10.1016/j.schres.2014.03.005
Vincenzi, B., Stock, S., Borba, C. P., Cleary, S. M., Oppenheim, C. E., Petruzzi, L. J., & Henderson, D. C. (2014). A randomized placebo-controlled pilot study of pravastatin as an adjunctive therapy in schizophrenia patients: effect on inflammation, psychopathology, cognition and lipid metabolism. Schizophrenia Research, 159(2–3), 395–403. https://doi.org/10.1016/j.schres.2014.08.021
Voineskos, A. N. (2015). Genetic underpinnings of white matter ‘connectivity’: heritability, risk, and heterogeneity in schizophrenia. Schizophrenia Research, 161(1), 50–60. https://doi.org/10.1016/j.schres.2014.03.034
Wang, X., Brieland, J. K., Kim, J. H., Chen, Y. J., O’Neal, J., O’Neil, S. P., & Song, S. K. (2013). Diffusion tensor imaging detects treatment effects of FTY720 in experimental autoimmune encephalomyelitis mice. NMR in Biomedicine, 26(12), 1742–1750. https://doi.org/10.1002/nbm.3012
Yarlagadda, A., Alfson, E., & Clayton, A. H. (2009). The blood brain barrier and the role of cytokines in neuropsychiatry. Psychiatry (Edgmont), 6(11), 18–22. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20049146.
Zhang, J., Chen, B., & Jian-rui, L. (2015). Treatment effect of risperidone alone and combined with N-acetyo-cysteine for first-episode schizophrenia patients. Journal of Clinical Psychiatry, 25, 394–396.
Acknowledgements
The authors would like to recognize David Spradley and Joan Showalter, whose recruitment efforts were essential for this study. The authors would like to thank Emily Good, Emmalee Metzler and Megan Gaunnac for helping to organize study visits. The authors would thank Dr. Alexander Radnovich for his participation in study visits and study design conceptualization. The authors would like to thank the Eskenazi Health-Midtown Community Mental Health center for their institutional support. The authors would also like to thank Fred Malloy for his work as a study rater. Financial support was provided by a Stanley Medical Research Institute (SMRI) grant (#11T-001, PI: Alan Breier). The SMRI had no further role in study design, data collection and analysis, the writing of the report, and in the decision to submit the paper for publication.
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Drs. Breier, Liffick, Francis, Vohs and Ms. Mehdiyoun conceived and designed the study. Drs. Breier, Liffick, Francis, Vohs, Ms. Mehdiyoun and Mr. Visco were responsible for data acquisition. Drs. Breier, Liffick, Francis, Vohs, and Hummer analyzed and interpreted the data. Drs. Francis, Liffick, Breier, and Hummer supervised the study. Drs. Breier, Liffick, Francis, Vohs, and Hummer drafted the manuscript. All authors contributed to and have approved the final manuscript.
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All procedures performed in this study were in accordance with the ethical standards of the Indiana University School of Medicine Institutional Review Board, the Indiana University Department of Psychiatry Data Safety Monitoring Board, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all patients for being included in the study.
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Dr. Liffick and Ms. Mehdiyoun were employees at Indiana University at the time the research was completed. They are currently employed at Eli Lilly and Company. They are current minor shareholders in the company. All other authors declare that they have no conflicts of interest.
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Francis, M.M., Hummer, T.A., Liffick, E. et al. Effects of fingolimod, a sphingosine-1-phosphate (S1P) receptor agonist, on white matter microstructure, cognition and symptoms in schizophrenia. Brain Imaging and Behavior 15, 1802–1814 (2021). https://doi.org/10.1007/s11682-020-00375-7
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DOI: https://doi.org/10.1007/s11682-020-00375-7