Prednisolone versus placebo addition in the treatment of patients with recent-onset psychotic disorder: a trial design

Springer Science and Business Media LLC - Tập 21 - Trang 1-13 - 2020
Lyliana G. Nasib1, Iris E. Sommer2,3, Inge Winter - van Rossum1, Jacqueline de Vries4, Shiral S. Gangadin1,2, Priscilla P. Oomen1,2, Gurmeet Judge5, Renske E. Blom1, Jurjen J. Luykx1,6,7,8, Nico J. M. van Beveren9,10,11, Natalie D. Veen5, Rune A. Kroken12,13, Erik L. Johnsen12,13
1Department of Psychiatry, UMC Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
2Cognitive Neurosciences, Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, Groningen, The Netherlands
3Department of Biological and Medical Psychology, University of Bergen , Bergen, Norway
4Reinier van Arkel, ‘s-Hertogenbosch, The Netherlands
5GGZ Delfland, Delft, The Netherlands
6Department of Translational Neuroscience, UMC Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
7Department of Psychiatry, ZNA Hospitals, Antwerp, Belgium
8Department of Psychiatry, SymforaMeander Hospital, Amersfoort, The Netherlands
9Antes Center for Mental Health Care, Rotterdam, The Netherlands
10Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands
11Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands
12NORMENT, Division of Psychiatry, Haukeland University Hospital, Bergen, Norway
13Department of Clinical Medicine, University of Bergen, Bergen, Norway

Tóm tắt

The symptom severity of a substantial group of schizophrenia patients (30–40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood–brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia. In total, 90 subjects aged 18–70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted. It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo. ClinicalTrials.gov, NCT02949232 and NCT03340909. Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014–000520-14 and 2017–000163-32.

Tài liệu tham khảo

Ayuso-Mateos J. Global burden of post-traumatic stress disorder in the year 2000: version 1 estimates: World Heal Organ; 2000. p. 1–11. Available from: http://wwwlive.who.int/entity/healthinfo/statistics/bod_posttraumaticstressdisorder.pdf.

Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “Just the Facts” 5. Treatment and prevention past, present, and future. Schizophr Res. 2010;122(1–3):1–23 Available from: https://doi.org/10.1016/j.schres.2010.05.025.

Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia. Arch Gen Psychiatry. 2007;64(10):1123 Available from: http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archpsyc.64.10.1123.

Haro JM, Altamura C, Corral R, Elkis H, Evans J, Krebs MO, et al. Understanding the course of persistent symptoms in schizophrenia: Longitudinal findings from the pattern study. Psychiatry Res. 2018;267(March):56–62.

Kitchen H, Rofail D, Heron L, Sacco P. Cognitive impairment associated with schizophrenia: a review of the humanistic burden. Adv Ther. 2012;29:148–62.

Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Psychiatry Interpers Biol Process. 1996;153:321–30.

Schmidt SJ, Mueller DR, Roder V. Social cognition as a mediator variable between neurocognition and functional outcome in schizophrenia: Empirical review and new results by structural equation modeling. Schizophr Bull. 2011;37(suppl 2):S41–54.

Nielsen RE, Levander S, Kjaersdam Telléus G, Jensen SOW, Østergaard Christensen T, Leucht S. Second-generation antipsychotic effect on cognition in patients with schizophrenia-a meta-analysis of randomized clinical trials [Internet]. Acta Psychiatrica Scandinavica. 2015;131:185–96 Available from: http://doi.wiley.com/10.1111/acps.12374.

Ripke S, Neale BM, Corvin A, Walters JT, Farh K-H, Holmans PA, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7.

Saito T, Kondo K, Iwayama Y, Shimasaki A, Aleksic B, Yamada K, et al. Replication and cross-phenotype study based upon schizophrenia GWASs data in the Japanese population: Support for association of MHC region with psychosis. Am J Med Genet Part B Neuropsychiatr Genet. 2014;165(5):421–7.

Sekar A, Bialas AR, De Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;11(5307589):177–83. Available from: http://www.nature.com/authors/editorial_policies/license.html#terms.

Jeppesen R, Benros ME. Autoimmune diseases and psychotic disorders. Front Psychiatry. 2019;10(march):1–11.

Fourrier C, Singhal G, Baune BT. Neuroinflammation and cognition across psychiatric conditions. CNS Spectr. 2019:1–12.

Van Kesteren CFMG, Gremmels H, De Witte LD, Hol EM, Van Gool AR, Falkai PG, et al. Immune involvement in the pathogenesis of schizophrenia: A meta-analysis on postmortem brain studies. Transl Psychiatry. 2017;7(3):e1075–11 Available from: https://doi.org/10.1038/tp.2017.4.

Müller N, Weidinger E, Leitner B, Schwarz MJ. The role of inflammation in schizophrenia. Front. Neurosci. 2015;9:372. https://doi.org/10.3389/fnins.2015.00372.

O'Donnell P. Cortical interneurons, immune factors and oxidative stress as early targets for schizophrenia. Eur J Neurosci. 2012;35(12):1866–70.

Plavén-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, Howes OD, et al. Positron emission tomography studies of the glial cell marker translocator protein in patients with psychosis: A meta-analysis using individual participant data. Biol Psychiatry. 2018;84(6):433–42 Available from: https://doi.org/10.1016/j.biopsych.2018.02.1171.

Bechter K, Reiber H, Herzog S, Fuchs D, Tumani H, Maxeiner HG. Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood-CSF barrier dysfunction. J Psychiatr Res. 2010;44(5):321–30 Available from: https://doi.org/10.1016/j.jpsychires.2009.08.008.

Gallego JA, Blanco EA, Husain-Krautter S, Madeline Fagen E, Moreno-Merino P, del Ojo-Jiménez JA, et al. Cytokines in cerebrospinal fluid of patients with schizophrenia spectrum disorders: New data and an updated meta-analysis. Schizophr Res. 2018;202:64–71. Available from: https://doi.org/10.1016/j.schres.2018.07.019.

Kay SR, Flazbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76.

Dahan S, Bragazzi NL, Yogev A, Bar-Gad M, Barak V, Amital H, et al. The relationship between serum cytokine levels and degree of psychosis in patients with schizophrenia. Psychiatry Res. 2018;268(June):467–72 Available from: https://doi.org/10.1016/j.psychres.2018.07.041.

Metcalf SA, Jones PB, Nordstrom T, Timonen M, Mäki P, Miettunen J, et al. Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study. Brain Behav Immun. 2017;59:253–9 Available from: https://doi.org/10.1016/j.bbi.2016.09.008.

Misiak B, Stańczykiewicz B, Kotowicz K, Rybakowski JK, Samochowiec J, Frydecka D. Cytokines and C-reactive protein alterations with respect to cognitive impairment in schizophrenia and bipolar disorder : A systematic review. Schizophr Res. 2018;192:16–29.

Schwarz E, Van Beveren NJM, Ramsey J, Leweke FM, Rothermundt M, Bogerts B, et al. Identification of subgroups of Schizophrenia patients with changes in either immune or growth factor and hormonal pathways. Schizophr Bull. 2014;40(4):787–95.

Najjar S, Pearlman DM. Neuroinflammation and white matter pathology in schizophrenia : systematic review. Schizophr Res. 2015;161(1):102–12 Available from: https://doi.org/10.1016/j.schres.2014.04.041.

Pasternak O, Kubicki M, Shenton ME. In vivo imaging of neuroinflammation in schizophrenia. Schizophr Res. 2016;173(3):200–12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24655651.

Gangadin SS, Nasib LG, Sommer IEC, Mandl RCW. MRI investigation of immune dysregulation in schizophrenia. Curr Opin Psychiatry. 2019;32(3):164–9.

Haijma SV, Van Haren N, Cahn W, Koolschijn PCMP, Hulshoff Pol HE, Kahn RS. Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects. Schizophr Bull. 2013;39(5):1129–38.

Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry. 2005;62(4):361–70 Available from: http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archpsyc.62.4.361.

Sommer IE, De Witte L, Begemann M, Kahn RS. Nonsteroidal anti-inflammatory drugs in schizophrenia: Ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73(4):414–9.

Broberg BV, Sommer IE, Benros ME, Glenthøj BY, Gasse C, Köhler-Forsberg O. Glucocorticoids and the risk of schizophrenia spectrum disorder in childhood and adolescence – A Danish nationwide study. Schizophr Res. 2018;199:116–22.

Çakici N, van Beveren NJM, Judge-Hundal G, Koola MM, Sommer IEC. An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis. Psychol Med. 2019:1–13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/31439071.

Chan MK, Guest PC, Levin Y, Umrania Y, Swarz E, Bahn S, et al. Converging evidence of blood-based biomarkerrs for schizophrenia: An update; 2011. p. 95–144.

Löwenberg M, Stahn C, Hommes DW, Buttgereit F. Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands. Steroids. 2008;73(9–10):1025–9.

Zéphir H, de Sèze J, Dujardin K, Dubois G, Cabaret M, Bouillaguet S, et al. Cognitive impact of mitoxantrone and methylprednisolone in multiple sclerosis: an open label study. Rev Neurol (Paris). 2008;164(1):47–52.

Spies CM, Bijlsma JWJ, Burmester GR, Buttgereit F. Pharmacology of glucocorticoids in rheumatoid arthritis. Curr Opin Pharmacol. 2010;10(3):302–7.

Ravindran V, Rachapalli S, Choy EH. Safety of medium- to long-term glucocorticoid therapy in rheumatoid arthritis: A meta-analysis. Rheumatology. 2009;48(7):807–11.

Fardet L, Petersen I, Nazareth I. Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care. Am J Psychiatry. 2012;(169):491–7.

Fardet L, Kassar A, Cabane J, Flahault A. Corticosteroid-induced adverse events in adults frequency, screening and prevention. Drug Saf. 2007;30(10):861–81.

Begemann MJH, Schutte MJL, Slot MIE, Doorduin J, Bakker PR, van Haren NEM, et al. Simvastatin augmentation for recent-onset psychotic disorder: A study protocol. BBA Clin. 2015;4:52–8. Available from: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L605287517.

Jones SH, Thornicroft G, Coffey M, Dunn G. A brief mental health outcome scale. Reliability and validity of the global assessment of functioning (GAF). Br J Psychiatry. 1995;166:654–9. https://doi.org/10.1192/bjp.166.5.654.

Addington D, Addington J, Maticka-Tyndale E. Assessing depression in schizophrenia: The Calgary Depression Scale. Br J Psychiatry. 1993;163(22):39–44.

Keefe RSE, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: Reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004;68(2–3):283–97.

Andreasen NC, Flaum M, Arndt S. The Comprehensive Assessment of Symptoms and History (CASH): an instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry. 1992;49(8):615–23.

Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The Development and Validation of a Structured Diagnostic Psychiatric Interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59:22–33.

Borm GF, Fransen J, Lemmens WAJG. A simple sample size formula for analysis of covariance in randomized clinical trials. J Clin Epidemiol. 2007;60(12):1234–8.

IBM. IBM SPSS Statistics Software for Windows, Version 25. IBM; 2017.

Smets I, Van Deun L, Bohyn C, van Pesch V, Vanopdenbosch L, Dive D, et al. Corticosteroids in the management of acute multiple sclerosis exacerbations. Acta Neurol Belg. 2017;117(3):623–33.

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