Ongoing Clinical Trials with Monoclonal Antibodies in Schizophrenia

2019/2020 Carlos Borges Chaves Clinical Trials with Monoclonal Antibodies in Schizophrenia: A Systematic Review Ensaios Clínicos com Anticorpos Monoclonais na Esquizofrenia: Uma Revisão Sistemática Maio, 2020 Mestrado Integrado em Medicina Área: Farmacologia, Psiquiatria Tipologia: Dissertação Trabalho efetuado sob a Orientação de: Professora Doutora Maria Augusta Vieira Coelho Trabalho organizado de acordo com as normas da revista: Schizophrenia Research Carlos Borges Chaves Clinical Trials with Monoclonal Antibodies in Schizophrenia: A Systematic Review Maio, 2020 UC Dissertação/Projeto (6º Ano) - DECLARAÇÃO DE INTEGRIDADE Eu, Carlos Borges Chaves, abaixo assinado, nº mecanográfico 201306111, estudante do 6º ano do Ciclo de Estudos Integrado em Medicina, na Faculdade de Medicina da Universidade do Porto, declaro ter atuado com absoluta integridade na elaboração deste projeto de opção. Neste sentido, confirmo que NÃO incorri em plágio (ato pelo qual um indivíduo, mesmo por omissão, assume a autoria de um determinado trabalho intelectual, ou partes dele). Mais declaro que todas as frases que retirei de trabalhos anteriores pertencentes a outros autores, foram referenciadas, ou redigidas com novas palavras, tendo colocado, neste caso, a citação da fonte bibliográfica. Faculdade de Medicina da Universidade do Porto, 19/03/2020 Assinatura conforme cartão de identificação: ________________________________________________ UC Dissertação/Projeto (6º Ano) – DECLARAÇÃO DE REPRODUÇÃO NOME Carlos Borges Chaves NÚMERO DE ESTUDANTE E-MAIL 201306111 [email protected] DESIGNAÇÃO DA ÁREA DO PROJECTO Farmacologia, Psiquiatria TÍTULO DISSERTAÇÃO/MONOGRAFIA (riscar o que não interessa) Clinical Trials with Monoclonal Antibodies in Schizophrenia: A Systematic Review ORIENTADOR Professora Doutora Maria Augusta Vieira Coelho ASSINALE APENAS UMA DAS OPÇÕES: É AUTORIZADA A REPRODUÇÃO INTEGRAL DESTE TRABALHO APENAS PARA EFEITOS DE INVESTIGAÇÃO, MEDIANTE DECLARAÇÃO ESCRITA DO INTERESSADO, QUE A TAL SE COMPROMETE. É AUTORIZADA A REPRODUÇÃO PARCIAL DESTE TRABALHO (INDICAR, CASO TAL SEJA NECESSÁRIO, Nº MÁXIMO DE PÁGINAS, ILUSTRAÇÕES, GRÁFICOS, ETC.) APENAS PARA EFEITOS DE INVESTIGAÇÃO, MEDIANTE DECLARAÇÃO ESCRITA DO INTERESSADO, QUE A TAL SE COMPROMETE. DE ACORDO COM A LEGISLAÇÃO EM VIGOR, (INDICAR, CASO TAL SEJA NECESSÁRIO, Nº MÁXIMO DE PÁGINAS, ILUSTRAÇÕES, GRÁFICOS, ETC.) NÃO É PERMITIDA A REPRODUÇÃO DE QUALQUER PARTE DESTE TRABALHO. Faculdade de Medicina da Universidade do Porto, 19/03/2020 Assinatura conforme cartão de identificação: ______________________________________________ Clinical Trials with Monoclonal Antibodies in Schizophrenia: A Systematic Review LIST OF AUTHORS: Corresponding author: Carlos Borges Chaves Bachelor in Basic Health Sciences Faculty of Medicine, University of Porto Address: Rua Condessa Paço Vitorino, n. 238, 4430-366, Vila Nova de Gaia, Portugal Phone: +351 915 315 399 Email: [email protected] Second author: Maria Augusta Vieira-Coelho PhD in Pharmacology and Therapeutics Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto ABSTRACT BACKGROUND: In recent years, there have been advances in the comprehension of schizophrenia aetiology, relating immune dysregulation as causal factor. Lifelong cytokine concentrations alterations are detected, which depend on the timing or severity of the disease. Several anti-inflammatory drugs have been tested as an adjunctive treatment to antipsychotics, showing beneficial effects. Monoclonal antibody therapies have also been suggested and tested, and this article aims to assess their efficacy. METHODS: A systematic review following PRISMA guidelines was conducted, searching in different databases with the intention of gathering all existing trials, concluded and ongoing, and case reports regarding monoclonal antibodies in schizophrenia. RESULTS: Overall, ten studies, three concluded and seven ongoing, and one case report were found. Only two drugs have been tested so far: Tocilizumab (targeting IL-6) in two trials, with cognition improvement seen in one study, and Canakinumab (targeting IL-1β) with positive symptomatology amelioration. Seven additional trials are currently testing Canakinumab, Siltuximab (targeting IL-6), Toclizumab, Natalizumab (targeting α4-integrin), Rituximab (targeting CD20) and Infliximab (targeting TNF-α). CONCLUSION: The results are promising, although more studies are needed. Stable schizophrenic patients with evidence of baseline inflammation were selected, but the drugs used target cytokines elevated solely in acute episodes. Thus, in the future judicious selection criteria, choice of drug and timing of action are required. KEYWORDS Schizophrenia; Psychosis; Inflammation; Treatment; Immunotherapy; Monoclonal Antibody 1. INTRODUCTION Immune dysregulation has been implicated in the disruption of neurodevelopmental pathways. In psychiatric patients, immune system (IS) abnormalities are evident and may be one factor contributing to the development of certain diseases.(Leboyer, Oliveira et al. 2016) One example is schizophrenia, possibly the most disabling and deleterious psychiatric disease, with a prevalence of 1% in the world population.(Strous and Shoenfeld 2006) It leads to a severe loss of productivity and is extremely expensive to both patient and family.(Strous and Shoenfeld 2006) In addition, patients usually have others comorbidities such as suicidal behaviour, cardiovascular disorders, diabetes and most importantly autoimmune diseases, which may decrease life expectancy in 10 to 15 years.(Leboyer, Oliveira et al. 2016) This illness can have different courses and presentations, although three clusters of clinical features are well characterized: positive symptoms (hallucinations, delusions,…), negative symptoms (blunted affect, social avoidance,…) and cognitive dysfunction.(Freedman 2003) Individuals presenting with mainly negative symptomatology may be diagnosed with deficit syndrome.(Carpenter, Heinrichs et al. 1988) Antipsychotics, the state-of-art of schizophrenia treatment, which act mainly by blocking D2-type dopamine receptors(Miyamoto, Duncan et al. 2005), are effective in reducing positive symptoms, although with high risk of short and long-term adverse effects.(Knight, Menkes et al. 2007) Negative symptoms and cognitive dysfunction are relatively resistant to these drugs.(Girgis, Kumar et al. 2014) There are two classes of antipsychotics: typical or first generation and atypical or second generation. This latter newer class, depending on the drug, may block different receptors such as serotoninergic.(Saha, Bo et al. 2016) Main adverse effects differ between these two classes due to their pharmacodynamics: first generation antipsychotics cause more extrapyramidal effects and second generation cause more weight gain and increase the risk of type 2 diabetes mellitus, being atypical drugs lightly better tolerated, but similar in terms of efficacy.(Leucht, Corves et al. 2009) Antipsychotic drugs prevent relapses, even though lack a disease-modifying effect.(Kroken, Sommer et al. 2018) For this reason, a treatment solely based on antipsychotic agents may not be the most effective way of treating resistant cases of schizophrenia. For the last decades, studies deepened the knowledge of schizophrenia in relation to IS. Prenatal, perinatal and childhood exposures to adversities, including maternal infections, nutritional deficiencies, obstetric complications, trauma, neglect or abuse increase the risk of all medical disorders in general, and mental diseases are not an exception. In such cases, one can observe persistent cytokines dysregulation, with increased levels of C reactive protein (CRP), IL-6 and TNF-α.(Coelho, Viola et al. 2014) Moreover, several reviews have stated that schizophrenia can be faced as an autoimmune disorder.(Knight, Menkes et al. 2007, Al-Diwani, Pollak et al. 2017) There is a case report of an aged man, with a diagnosis of lymphocytic leukaemia with no psychiatric history, who received an allogeneic peripheral blood stem cell transplant from a schizophrenic brother. Few weeks later, the patient developed acute psychotic symptoms.(Sommer, van Bekkum et al. 2015) A reverse case is also described, where a young adult man with treatment-resistant schizophrenia was diagnosed with acute myeloid leukaemia, which was treated with bone marrow transplantation from a healthy donor. During the first year, this patient showed remarkable improvement of the psychotic state and social functioning in the absence of antipsychotics.(Miyaoka, Wake et al. 2017) Even though one cannot conclude a causal relationship, IS may have played a role in these cases. So far, experts have found that schizophrenic patients have alterations in the number of immune cell numbers, inflammatory markers and antibody titres in the blood and cerebrospinal fluid.(Kirkpatrick and Miller 2013) Focusing mainly on immune markers, these may vary according to the clinical status of the patient, and specialists divide them in two different groups. First, state markers, namely IL-1β, IL-6 and TGF-β, whose blood levels are increased during exacerbations of symptoms, when compared to controls, but stabilized when treated with antipsychotics.(Miller, Buckley et al. 2011) Second, trait markers, including IL-12, IFN-γ and TNF-α, whose levels are systematically increased in acutely and chronically ill patients even during clinical stability, when compared to controls.(Miller, Buckley et al. 2011) In some cases, different autoantibodies may be found, including anticardiolipin and N-methyl-D-aspartate receptor (NMDAR) autoantibodies, whose role in schizophrenia is not clear yet, existing significant heterogeneity in the literature.(Ezeoke, Mellor et al. 2013) However, there is an entity with increasing scientific interest which is NDMAR encephalitis, mediated by autoantibodies against NDMAR, where 75% of patients may present initially with pure psychiatric symptoms and no accompanying neurological signs, being most of the times misdiagnosed as a primary psychiatric disorder.(Dalmau, Gleichman et al. 2008) A NMDAR hypofunction model of schizophrenia is also hypothesised.(Adell, Jimenez-Sanchez et al. 2012) Literature mentions evidence of neuroinflammation, what explains underlying structural and functional brain alterations. This has been homogeneously proved through positron emission tomography, showing activation of microglia.(Girgis, Kumar et al. 2014, Miller and Goldsmith 2017) In addition, in a recent meta-analysis clozapine showed being the most efficient antipsychotic when compared to the others, in both treatment-resistant and non-resistant schizophrenia.(Mizuno, McCutcheon et al. 2019) In fact, this drug has shown several immunosuppressive properties, as well as, haloperidol.(Strous and Shoenfeld 2006, Knight, Menkes et al. 2007) For these abovementioned reasons, the pathophysiology of schizophrenia may in part have an inflammatory aetiology. In order to prove this, several trials studied the efficacy of certain agents with anti-inflammatory properties such as aspirin, celecoxib, oestrogen, minocycline, N-acetylcysteine, fatty acids, davunetide, azathioprine and methotrexate, as an adjunctive treatment to antipsychotics, and some had showed significant symptomatic improvement.(Miller and Buckley 2016) Furthermore, two of these trials had assessed baseline serum values of cytokines, before and after drug administration, and patients who had increased inflammation levels before treatment had better outcomes, in terms of pathophysiology.(Muller, Ulmschneider et al. 2004, Laan, Grobbee et al. 2010) There is also one trial described that used in vitro activated immune cells, also with beneficial effects and decrease of cytokines levels.(Wank 2002) Cytokine based immunotherapy is already used in a myriad of autoimmune disorders and certain cancers.(Miller and Buckley 2016) There is a recent study comparing the prevalence of psychosis as an adverse effect of treatments using monoclonal antibodies (MAb) targeting immune molecules and bevacizumab, an anti-vascular endothelial growth factor MAb, not targeting the immune system. Findings of this study showed that, albeit rarely, modulating the immune system may cause psychosis, when compared to bevacizumab.(Essali, Goldsmith et al. 2019) Moreover, there is a study related to the efficacy of adjunctive infliximab treatment, a MAb against TNF-α, in treatment-resistant depression, whose results were promising.(Mehta, Raison et al. 2013) Specifically in schizophrenia, one study using recombinant human IFN-γ1B showed improvement of symptomatology in two patients.(Gruber, Bunse et al. 2014) There are several potential advantages of MAb immunotherapy over other anti-inflammatory agents. Most importantly they are more potent and do not have any off-target effects, acting only on specific cytokines, when compared to aspirin, for example.(Miller and Buckley 2016) Besides, they will help bringing novel knowledge regarding the aetiology of inflammation in schizophrenia.(Miller and Buckley 2016) Furthermore, mounting evidence underlines the linkage of negative symptoms and increased inflammatory cytokines.(Goldsmith, Haroon et al. 2018) Being antipsychotics ineffective against patients demonstrating mainly negative symptomatology, other treatments must be sought. To date, it is known that IL-1β, IL-2, IL-6, TNF-α, IFN-γ and chemokine CCL1 may be potential treatment targets using MAbs.(Miller and Buckley 2016, Muller 2018) Another possible target may be inhibitors of microglial activation.(Inglese and Petracca 2015) In this review, firstly, the authors will search all concluded trials regarding schizophrenia treatment with MAbs, ultimately assessing the individual results. Secondly, all case reports and ongoing trials will be described. Finally, the authors will briefly discuss the efficacy of such therapies so far and what can be ameliorated for the future. 2. MATERIALS AND METHODS A systematic review was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalyses) guidelines. Being a novel discussion, the aim of this research was to gather all trials testing the efficacy of MAbs in schizophrenia, without considering specific study characteristics. Study quality evaluation was performed using the Jadad Scale. The eligibility criteria were: trials using MAbs; trials in humans; schizophrenic or schizophrenia spectrum patients; primary outcome being improvement in psychopathology and cognition or inflammatory markers. The exclusion criteria were: immunosuppressive drugs trials not including MAbs; trials in animals; psychotic disorders other than from schizophrenia spectrum. A primary search was performed, by one author first and replicated by a second, in PubMed, Web of Science, Scopus and Cochrane, in order to include all concluded trials regarding MAb treatment in schizophrenia and schizophrenia spectrum disorders, until March 2020. There was no restriction on language of publication. The query was the following (“schizophrenia” OR “schizophrenia spectrum” OR “schizoaffective disorder” OR “psychotic disorder” OR “psychosis”) AND (“monoclonal antibody” OR “monoclonal antibody treatment” OR “monoclonal antibody therapy”). In the selection phase, titles of articles were read and selected according to their relevance to the study and eligibility criteria. As the search was performed in several databases, duplicates were eliminated in a second phase. The remnant studies were assessed and selected according to their relation to the aim of this study. Additional searches were carried out in order to include case reports and ongoing or under recruitment trials. Finally, after a thorough literature assessment, other existing trials were added. 3. RESULTS The main search method used by the authors gathered a total of 450 articles. After screening titles according to eligibility criteria, 429 articles were excluded. As the search was made in different databases, duplicates had to be removed, decreasing the number of selected articles from 21 to 12. The full text of these last selected articles was retrieved, leading to the final result of 2 concluded trials, which met the inclusion criteria. Figure 1 shows a flowchart describing this primary search method. Secondary searches and literature assessment led to the additional inclusion of 1 concluded trial, 1 case report and 7 ongoing trials. All in all, the authors gathered 10 trials, 3 concluded and 7 ongoing trials, of which two active and five recruiting, and 1 case report. Being MAb treatment in schizophrenia relatively recent and untouched, one must be aware of the limitations of the present review. Table 1 shows study characteristics and trial evaluation according to Jadad Scale. 3.1 Concluded trials Three studies about the efficacy of MAbs in schizophrenic patients have been published, two with Tocilizumab and one with Canakinumab, all of them as an adjunctive therapy to antipsychotics. IL-6 is a pro-inflammatory cytokine synthetized by leukocytes in the blood and by microglia and astrocytes in the central nervous system (CNS). It is related with decreased hippocampus volume and deficit syndrome.(Miller, Buckley et al. 2011) Tocilizumab is a humanized anti-IL-6 receptor MAb, which was studied in an 8 week open-label trial.(Miller, Dias et al. 2016) This drug is approved by the FDA for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, being administered every 4 weeks intravenously.(Miller, Dias et al. 2016) Five patients with a diagnosis of either schizophrenia or schizoaffective disorder treated with non-clozapine antipsychotics received two doses of 4mg/Kg of Tocilizumab, at baseline and week 4.(Miller, Dias et al. 2016) The primary outcomes were the assessment of: psychopathology with Positive and Negative Syndrome Scale(Kay, Fiszbein et al. 1987) (PANSS); cognition using Brief Assessment of Cognition in Schizophrenia(Keefe, Goldberg et al. 2004) (BACS); fasting serum high-sensitivity C-reactive protein (hsCRP) and cytokines levels, at baseline, week 2, 4 and 8.(Miller, Dias et al. 2016) Overall, adjunctive Tocilizumab was related to a significant improvement in cognition, namely verbal fluency and digit symbol coding according to BACS score. However, there was no beneficial effect on psychopathology, hsCRP or cytokines levels, apart from IL-6 levels that, not surprisingly, increased because of its receptor blockage.(Miller, Dias et al. 2016) The authors stated that evidence of baseline inflammatory markers was not an inclusion criterion what may have decreased the benefit of this drug. Moreover, in rheumatoid arthritis the dose is 8 mg/Kg after the first infusion, and in this trial half of this dose was used, what may have masked any additional improvement.(Miller, Dias et al. 2016) Figure 1. Flow chart of the study selection process. A second trial was executed, where 36 patients with a diagnosis of either schizophrenia or schizoaffective disorder, were randomized and administered double blindly with three doses of 8 mg/Kg Tocilizumab or placebo, normal saline, one each month.(Girgis, Ciarleglio et al. 2018) Patients taking clozapine or other medications that directly or indirectly have anti-inflammatory effects were excluded, as well as, patients who had inflammatory or autoimmune disorders or recent severe infections.(Girgis, Ciarleglio et al. 2018) The primary outcome was PANSS assessment. In addition, other scores were used as a secondary outcome. Measurements of CRP and cytokines levels were performed at week 2, 4, 8 and 12.(Girgis, Ciarleglio et al. 2018) There was no relevant effects on PANSS, CRP or cytokines levels, being consistent with the open-label trial discussed previously. One possible explanation given by the authors is that Tocilizumab may not cross the blood-brain barrier.(Girgis, Ciarleglio et al. 2018) Data suggests that IL-6 is a state marker(Miller, Buckley et al. 2011), what means that it is elevated during acute relapses or in first episode psychosis, normalizing with treatment, so this drug may not be ideal in chronic stable patients.(Girgis, Ciarleglio et al. 2018) IL-1β mRNA and protein levels are substantially increased in blood, inflammatory cells and CNS of patients with first episode psychosis and schizophrenia.(Weickert T. 2019) Canakinumab is a human anti-IL-1β MAb used in the treatment of juvenile idiopathic arthritis and other inflammatory conditions. A randomized double-blind trial using Canakinumab and placebo was conducted, where 27 patients with a diagnosis of schizophrenia or schizoaffective disorder, with elevated peripheral inflammatory markers, were administered with a single dose of 150 mg of Canakinumab or placebo subcutaneously.(Weickert T. 2019) Peripheral hsCRP levels and PANSS were assessed before treatment and at week 4 and 8.(Weickert T. 2019) There was a significant reduction of hsCRP and positive symptomatology in the Canakinumab group, but no improvement was seen in negative psychopathology.(Weickert T. 2019) AUTHOR INFORMATION PACK 19 Mar 2020 www.elsevier.com/locate/schres 2 EDITORIAL BOARD . Editor-in-Chief Matcheri Keshavan, MD, BETH ISRAEL DEACONESS MEDICAL CENTER, Boston, Massachusetts, 02215 Co-Founding Editors H.A. Nasrallah, Saint Louis University School of Medicine, 1438 South Grand Blvd., Cincinnati, Ohio, 63104 USA L.E. 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If quoting directly from a previously published method, use quotation marks and also cite the source. Any modifications to existing methods should also be described. AUTHOR INFORMATION PACK 19 Mar 2020 www.elsevier.com/locate/schres 7 Theory/calculation A Theory section should extend, not repeat, the background to the article already dealt with in the Introduction and lay the foundation for further work. In contrast, a Calculation section represents a practical development from a theoretical basis. Results Results should be clear and concise. Discussion This should explore the significance of the results of the work, not repeat them. A combined Results and Discussion section is often appropriate. Avoid extensive citations and discussion of published literature. Conclusions The main conclusions of the study may be presented in a short Conclusions section, which may stand alone or form a subsection of a Discussion or Results and Discussion section. Appendices If there is more than one appendix, they should be identified as A, B, etc. Formulae and equations in appendices should be given separate numbering: Eq. (A.1), Eq. (A.2), etc.; in a subsequent appendix, Eq. (B.1) and so on. Similarly for tables and figures: Table A.1; Fig. A.1, etc. Vitae Submit a short (maximum 100 words) biography of each author, along with a passport-type photograph accompanying the other figures. Please provide the biography in an editable format (e.g. Word), not in PDF format. Essential title page information • Title. Concise and informative. Titles are often used in information-retrieval systems. Avoid abbreviations and formulae where possible. • Author names and affiliations. Please clearly indicate the given name(s) and family name(s) of each author and check that all names are accurately spelled. You can add your name between parentheses in your own script behind the English transliteration. Present the authors' affiliation addresses (where the actual work was done) below the names. Indicate all affiliations with a lowercase superscript letter immediately after the author's name and in front of the appropriate address. Provide the full postal address of each affiliation, including the country name and, if available, the e-mail address of each author. • Corresponding author. Clearly indicate who will handle correspondence at all stages of refereeing and publication, also post-publication. This responsibility includes answering any future queries about Methodology and Materials. Ensure that the e-mail address is given and that contact details are kept up to date by the corresponding author. • Present/permanent address. If an author has moved since the work described in the article was done, or was visiting at the time, a 'Present address' (or 'Permanent address') may be indicated as a footnote to that author's name. The address at which the author actually did the work must be retained as the main, affiliation address. Superscript Arabic numerals are used for such footnotes. Abstract A concise and factual abstract is required. The abstract should state briefly the purpose of the research, the principal results and major conclusions. An abstract is often presented separately from the article, so it must be able to stand alone. For this reason, References should be avoided, but if essential, then cite the author(s) and year(s). Also, non-standard or uncommon abbreviations should be avoided, but if essential they must be defined at their first mention in the abstract itself. Keywords Immediately after the abstract, provide a maximum of 6 keywords, using American spelling and avoiding general and plural terms and multiple concepts (avoid, for example, 'and', 'of'). Be sparing with abbreviations: only abbreviations firmly established in the field may be eligible. These keywords will be used for indexing purposes. Abbreviations Define abbreviations that are not standard in this field in a footnote to be placed on the first page of the article. Such abbreviations that are unavoidable in the abstract must be defined at their first mention there, as well as in the footnote. Ensure consistency of abbreviations throughout the article. AUTHOR INFORMATION PACK 19 Mar 2020 www.elsevier.com/locate/schres 8 Acknowledgements Collate acknowledgements in a separate section at the end of the article before the references and do not, therefore, include them on the title page, as a footnote to the title or otherwise. List here those individuals who provided help during the research (e.g., providing language help, writing assistance or proof reading the article, etc.). Math formulae Please submit math equations as editable text and not as images. Present simple formulae in line with normal text where possible and use the solidus (/) instead of a horizontal line for small fractional terms, e.g., X/Y. In principle, variables are to be presented in italics. Powers of e are often more conveniently denoted by exp. Number consecutively any equations that have to be displayed separately from the text (if referred to explicitly in the text). Footnotes Footnotes should be used sparingly. Number them consecutively throughout the article. Many word processors can build footnotes into the text, and this feature may be used. Otherwise, please indicate the position of footnotes in the text and list the footnotes themselves separately at the end of the article. Do not include footnotes in the Reference list. Artwork Electronic artwork General points • Make sure you use uniform lettering and sizing of your original artwork. • Embed the used fonts if the application provides that option. • Aim to use the following fonts in your illustrations: Arial, Courier, Times New Roman, Symbol, or use fonts that look similar. • Number the illustrations according to their sequence in the text. • Use a logical naming convention for your artwork files. • Provide captions to illustrations separately. • Size the illustrations close to the desired dimensions of the published version. • Submit each illustration as a separate file. • Ensure that color images are accessible to all, including those with impaired color vision. A detailed guide on electronic artwork is available. You are urged to visit this site; some excerpts from the detailed information are given here. Formats If your electronic artwork is created in a Microsoft Office application (Word, PowerPoint, Excel) then please supply 'as is' in the native document format. Regardless of the application used other than Microsoft Office, when your electronic artwork is finalized, please 'Save as' or convert the images to one of the following formats (note the resolution requirements for line drawings, halftones, and line/halftone combinations given below): EPS (or PDF): Vector drawings, embed all used fonts. TIFF (or JPEG): Color or grayscale photographs (halftones), keep to a minimum of 300 dpi. TIFF (or JPEG): Bitmapped (pure black & white pixels) line drawings, keep to a minimum of 1000 dpi. TIFF (or JPEG): Combinations bitmapped line/half-tone (color or grayscale), keep to a minimum of 500 dpi. Please do not: • Supply files that are optimized for screen use (e.g., GIF, BMP, PICT, WPG); these typically have a low number of pixels and limited set of colors; • Supply files that are too low in resolution; • Submit graphics that are disproportionately large for the content. Color artwork Please make sure that artwork files are in an acceptable format (TIFF (or JPEG), EPS (or PDF), or MS Office files) and with the correct resolution. If, together with your accepted article, you submit usable color figures then Elsevier will ensure, at no additional charge, that these figures will appear in color online (e.g., ScienceDirect and other sites) regardless of whether or not these illustrations are reproduced in color in the printed version. For color reproduction in print, you will receive information regarding the costs from Elsevier after receipt of your accepted article. Please indicate your preference for color: in print or online only. Further information on the preparation of electronic artwork. AUTHOR INFORMATION PACK 19 Mar 2020 www.elsevier.com/locate/schres 9 Figure captions Ensure that each illustration has a caption. Supply captions separately, not attached to the figure. A caption should comprise a brief title (not on the figure itself) and a description of the illustration. Keep text in the illustrations themselves to a minimum but explain all symbols and abbreviations used. Tables Please submit tables as editable text and not as images. Tables can be placed either next to the relevant text in the article, or on separate page(s) at the end. Number tables consecutively in accordance with their appearance in the text and place any table notes below the table body. Be sparing in the use of tables and ensure that the data presented in them do not duplicate results described elsewhere in the article. Please avoid using vertical rules and shading in table cells. References Citation in text Please ensure that every reference cited in the text is also present in the reference list (and vice versa). Any references cited in the abstract must be given in full. Unpublished results and personal communications are not recommended in the reference list, but may be mentioned in the text. If these references are included in the reference list they should follow the standard reference style of the journal and should include a substitution of the publication date with either 'Unpublished results' or 'Personal communication'. Citation of a reference as 'in press' implies that the item has been accepted for publication. Web references As a minimum, the full URL should be given and the date when the reference was last accessed. Any further information, if known (DOI, author names, dates, reference to a source publication, etc.), should also be given. Web references can be listed separately (e.g., after the reference list) under a different heading if desired, or can be included in the reference list. Data references This journal encourages you to cite underlying or relevant datasets in your manuscript by citing them in your text and including a data reference in your Reference List. Data references should include the following elements: author name(s), dataset title, data repository, version (where available), year, and global persistent identifier. Add [dataset] immediately before the reference so we can properly identify it as a data reference. The [dataset] identifier will not appear in your published article. References in a special issue Please ensure that the words 'this issue' are added to any references in the list (and any citations in the text) to other articles in the same Special Issue. Reference management software Most Elsevier journals have their reference template available in many of the most popular reference management software products. These include all products that support Citation Style Language styles, such as Mendeley. Using citation plug-ins from these products, authors only need to select the appropriate journal template when preparing their article, after which citations and bibliographies will be automatically formatted in the journal's style. If no template is yet available for this journal, please follow the format of the sample references and citations as shown in this Guide. If you use reference management software, please ensure that you remove all field codes before submitting the electronic manuscript. More information on how to remove field codes from different reference management software. Users of Mendeley Desktop can easily install the reference style for this journal by clicking the following link: http://open.mendeley.com/use-citation-style/schizophrenia-research When preparing your manuscript, you will then be able to select this style using the Mendeley plugins for Microsoft Word or LibreOffice. Reference style Text: All citations in the text should refer to: 1. Single author: the author's name (without initials, unless there is ambiguity) and the year of publication; 2. Two authors: both authors' names and the year of publication; 3. Three or more authors: first author's name followed by 'et al.' and the year of publication. Citations may be made directly (or parenthetically). Groups of references can be listed either first alphabetically, then chronologically, or vice versa. AUTHOR INFORMATION PACK 19 Mar 2020 www.elsevier.com/locate/schres 10 Examples: 'as demonstrated (Allan, 2000a, 2000b, 1999; Allan and Jones, 1999)…. Or, as demonstrated (Jones, 1999; Allan, 2000)… Kramer et al. (2010) have recently shown …' List: References should be arranged first alphabetically and then further sorted chronologically if necessary. More than one reference from the same author(s) in the same year must be identified by the letters 'a', 'b', 'c', etc., placed after the year of publication. Examples: Reference to a journal publication: Van der Geer, J., Hanraads, J.A.J., Lupton, R.A., 2010. The art of writing a scientific article. J. Sci. Commun. 163, 51–59. https://doi.org/10.1016/j.Sc.2010.00372. Reference to a journal publication with an article number: Van der Geer, J., Hanraads, J.A.J., Lupton, R.A., 2018. The art of writing a scientific article. Heliyon. 19, e00205. https://doi.org/10.1016/j.heliyon.2018.e00205. Reference to a book: Strunk Jr., W., White, E.B., 2000. The Elements of Style, fourth ed. Longman, New York. Reference to a chapter in an edited book: Mettam, G.R., Adams, L.B., 2009. How to prepare an electronic version of your article, in: Jones, B.S., Smith , R.Z. (Eds.), Introduction to the Electronic Age. E-Publishing Inc., New York, pp. 281–304. Reference to a website: Cancer Research UK, 1975. Cancer statistics reports for the UK. http://www.cancerresearchuk.org/ aboutcancer/statistics/cancerstatsreport/ (accessed 13 March 2003). Reference to a dataset: [dataset] Oguro, M., Imahiro, S., Saito, S., Nakashizuka, T., 2015. Mortality data for Japanese oak wilt disease and surrounding forest compositions. Mendeley Data, v1. https://doi.org/10.17632/ xwj98nb39r.1. Journal abbreviations source Journal names should be abbreviated according to the List of Title Word Abbreviations. Video Elsevier accepts video material and animation sequences to support and enhance your scientific research. Authors who have video or animation files that they wish to submit with their article are strongly encouraged to include links to these within the body of the article. This can be done in the same way as a figure or table by referring to the video or animation content and noting in the body text where it should be placed. All submitted files should be properly labeled so that they directly relate to the video file's content. In order to ensure that your video or animation material is directly usable, please provide the file in one of our recommended file formats with a preferred maximum size of 150 MB per file, 1 GB in total. Video and animation files supplied will be published online in the electronic version of your article in Elsevier Web products, including ScienceDirect. Please supply 'stills' with your files: you can choose any frame from the video or animation or make a separate image. These will be used instead of standard icons and will personalize the link to your video data. For more detailed instructions please visit our video instruction pages. Note: since video and animation cannot be embedded in the print version of the journal, please provide text for both the electronic and the print version for the portions of the article that refer to this content. Data visualization Include interactive data visualizations in your publication and let your readers interact and engage more closely with your research. Follow the instructions here to find out about available data visualization options and how to include them with your article. Supplementary material Supplementary material such as applications, images and sound clips, can be published with your article to enhance it. Submitted supplementary items are published exactly as they are received (Excel or PowerPoint files will appear as such online). Please submit your material together with the article and supply a concise, descriptive caption for each supplementary file. If you wish to make changes to supplementary material during any stage of the process, please make sure to provide an updated file. Do not annotate any corrections on a previous version. Please switch off the 'Track Changes' option in Microsoft Office files as these will appear in the published version. Data linking If you have made your research data available in a data repository, you can link your article directly to the dataset. Elsevier collaborates with a number of repositories to link articles on ScienceDirect with relevant repositories, giving readers access to underlying data that gives them a better understanding of the research described. AUTHOR INFORMATION PACK 19 Mar 2020 www.elsevier.com/locate/schres 11 There are different ways to link your datasets to your article. When available, you can directly link your dataset to your article by providing the relevant information in the submission system. For more information, visit the database linking page. For supported data repositories a repository banner will automatically appear next to your published article on ScienceDirect. In addition, you can link to relevant data or entities through identifiers within the text of your manuscript, using the following format: Database: xxxx (e.g., TAIR: AT1G01020; CCDC: 734053; PDB: 1XFN). AFTER ACCEPTANCE Online proof correction To ensure a fast publication process of the article, we kindly ask authors to provide us with their proof corrections within two days. Corresponding authors will receive an e-mail with a link to our online proofing system, allowing annotation and correction of proofs online. The environment is similar to MS Word: in addition to editing text, you can also comment on figures/tables and answer questions from the Copy Editor. Web-based proofing provides a faster and less error-prone process by allowing you to directly type your corrections, eliminating the potential introduction of errors. If preferred, you can still choose to annotate and upload your edits on the PDF version. All instructions for proofing will be given in the e-mail we send to authors, including alternative methods to the online version and PDF. We will do everything possible to get your article published quickly and accurately. Please use this proof only for checking the typesetting, editing, completeness and correctness of the text, tables and figures. Significant changes to the article as accepted for publication will only be considered at this stage with permission from the Editor. It is important to ensure that all corrections are sent back to us in one communication. Please check carefully before replying, as inclusion of any subsequent corrections cannot be guaranteed. Proofreading is solely your responsibility. Offprints The corresponding author will, at no cost, receive a customized Share Link providing 50 days free access to the final published version of the article on ScienceDirect. The Share Link can be used for sharing the article via any communication channel, including email and social media. For an extra charge, paper offprints can be ordered via the offprint order form which is sent once the article is accepted for publication. Both corresponding and co-authors may order offprints at any time via Elsevier's Author Services. Corresponding authors who have published their article gold open access do not receive a Share Link as their final published version of the article is available open access on ScienceDirect and can be shared through the article DOI link. AUTHOR INQUIRIES Visit the Elsevier Support Center to find the answers you need. Here you will find everything from Frequently Asked Questions to ways to get in touch. You can also check the status of your submitted article or find out when your accepted article will be published. © Copyright 2018 Elsevier | https://www.elsevier.com