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

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

UC Dissertação/Projeto (6º Ano) -

D

I

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

UC Dissertação/Projeto (6º Ano) – DECLARAÇÃO DE REPRODUÇÃO

NOME

Carlos Borges Chaves

NÚMERO DE ESTUDANTE E-MAIL

201306111 carlosbchaves123@gmail.com

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

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: carloschaves123@gmail.com Second author:

Maria Augusta Vieira-Coelho

PhD in Pharmacology and Therapeutics

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 CD-20) 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 Meta-Analyses) 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)

3.2 Case report

The authors found 1 case report describing a 23 year old woman with fistulising Chron’s disease, requiring optimization of immunosuppression. The dose of prednisolone was increased from 5 mg/day to 50 mg/day adding azathioprine 100 mg/day. Seven weeks after, the patient developed psychotic symptoms being treated with amisulpride 600 mg/day and quetiapine 50 mg/day, with no improvement after seven weeks. In this phase, quetiapine dose was increased to 700 mg/day and amilsupride was switched by haloperidol 20 mg/day. In the following 4 weeks, symptoms ameliorated, although haloperidol had to be discontinued due to extrapyramidal adverse effects. Steroid-induced psychosis was suspected, and for this reason prednisolone was replaced by budenoside 9 mg/day. However, psychotic state and Chron’s disease were not effectively controlled, so doctors decided to administer 300 mg of Infliximab intravenously twice each two weeks. There was clinical improvement of both diseases during the following 6 weeks, being discharged at this point with quetiapine 250 mg/day, budenoside 9 mg/day and azathioprine 100 mg/day. In the outpatient setting, 28 weeks after, the patient denied any psychotic symptom with good control of Chron’s disease. The case reporters excluded steroid-induced psychosis, considering the diagnosis of schizophrenia as the most likely. They concluded that the reduction of psychotic symptoms is related with the suppression of cytokine release by Infliximab.(Reimer, Fink et al. 2009)

3.3 Ongoing trials

Seven ongoing trials were identified, three in the USA, two in the UK, one in Australia and one in Sweden. In the Australian study, Dr. Thomas Weickert, currently the main investigator, plans to randomize 30 patients, with a diagnosis of schizophrenia or schizoaffective disorder, to a subcutaneous administration of 180 mg Canakinumab or placebo, as an adjunctive treatment to antipsychotics. One inclusion criteria is evidence of elevated neutrophil-lymphocyte ratio greater than 2 or an elevated IL-1β ELISA assay. The aim of this trial is to study improvement of language, memory, and symptoms in schizophrenia. According to official data, Canakinumab is useful in reducing harmful by-products of infection. The primary outcome is evaluation of PANSS. (CATS study; ACTRN12615000635561).

Dr. Brian Miller is currently leading two trials at Augusta University in Georgia, USA. One is a double-blind randomized trial, whose intervention is the administration of 11 mg/kg Siltuximab, a recombinant chimeric MAb against IL-6 used in Castleman disease, or placebo as an adjunctive treatment. Investigators proposed a 9 week trial, with 30 participants, with schizophrenia or schizoaffective disorder, and evidence of inflammation in the blood, hsCRP>0,5mg/dL. The primary outcome is assessment of cognition using BACS. (NCT02796859). The second trial aims to determine the safety, tolerability and efficacy of Tocilizumab. Twenty stable outpatients with hsCRP>0,5mg/dL, will be double-blindly randomized to be treated with 4 mg/kg Tocilizumab or placebo for 12 weeks, as an adjunctive treatment. The primary outcome is to measure improvements in cognition using BACS. (NCT02874573).

Dr. Oliver Howes is responsible for a quadruple-blind trial in London, which plans to randomize 60 symptomatic patients with schizophrenia or other psychotic disorder. The intervention is to administer Natalizumab, a humanized MAb against the cell adhesion molecule α4-integrin used for the treatment of multiple sclerosis and Crohn's disease, or placebo. The primary outcome is to measure the availability of translocator protein (TSPO) before and after drug administration, using positron emission tomography. TSPO is a mitochondrial protein, which is expressed by microglia when in the activated state.(Ching, Kuhnast et al. 2012, Miller and Goldsmith 2017) (NCT03093064).

Dr. Alastdair Coles and Dr. Belinda Lennox proposed a double-blind trial in the UK to test the efficacy of 2g/kg intravenous immunoglobulin (IVIG) plus two doses of 1g Rituximab or placebo in the treatment of acute psychosis associated with anti-neuronal membrane autoantibodies. Rituximab is a humanized MAb used in haematological malignancies. Eighty patients will be randomized in the trial, whose primary outcome is to measure how long it takes to start disease remission, defined as PANSS ≤ 3. (NCT03194815).

Dr. David Goldsmith is leading a triple-blind trial with Infliximab. According to official data, “inflammatory stimuli

decrease neural activity in the ventral striatum and decrease connectivity in reward-relevant neural circuitry” and that

“some patients with schizophrenia reliably exhibit elevated concentrations of inflammatory markers and that

inflammatory cytokines may be related to negative symptoms including decreased motivation”. Based on this premises,

the trial will consist in the randomization of 20 patients with elevated CRP >3mg/L, to the administration of 5mg/Kg Infliximab or placebo, being the primary outcome the measurement of mean change in reward circuitry connectivity, up to 10 days after infusion. (NCT03818516).

Finally, Dr. Susanne Bejerot is organizing an open trial which will investigate whether a single dose of 1000 mg Rituximab significantly improves psychiatric symptoms of adult schizophrenia spectrum disorder patients. Twelve participants will enrol, and the respective PANSS will be assessed at week 20 as primary outcome. (NCT03983018). 4. DISCUSSION AND CONCLUSIONS

MAb immunotherapy may be beneficial to modify or rebalance the IS, being useful in disturbances where IS dysregulation is seen, such as schizophrenia.(Strous and Shoenfeld 2006) However, great part of patients do not manifest aspects of autoimmune or immunological aberrations, what means that schizophrenia may be a group of different subtypes of conditions.(Strous and Shoenfeld 2006) Because of this, it is unlikely that responses to one type of treatment would be similar in every patient.(Knight, Menkes et al. 2007) In fact, only around 40% of patients with schizophrenia have elevated cytokines in both peripheral blood and in the CNS.(Weickert T. 2019) Moreover, first episode illness may be the phase that more likely coincides with autoimmune processes, thus offering the best chance for effective immunosuppression.(Knight, Menkes et al. 2007) Evidence suggests that patients may show different immune phenotypes, and each one of these may predict treatment response to different therapies.(Khandaker, Dantzer et al. 2017) So, some reviews defend that each patient must be evaluated in order to create their immune signature, so as to more personalized anti-inflammatory therapies may be administered.(Miller and Goldsmith 2017)

Overall, regular anti-inflammatory agents showed being beneficial in treatment-resistant schizophrenic patients. Nevertheless, MAb immunotherapy has several potential advantages over these at the expense of some adverse effects. Miller et al. described in a review some advantages: no relevant off-target effects; direct testing of the hypothesis that inflammation has an aetiological role in schizophrenia; more potent anti-inflammatory properties than other agents; intravenous infusion that implies treatment adherence, contrarily to oral administration of other treatments; and also some disadvantages: serious adverse effects due to immunosuppression as life-threatening infections, demyelinating disorders, ulcers and malignancies; high cost of MAb treatment, which may be higher than $1000 per dose; requirement of better staff management and resources due to intravenous administration.(Miller and Buckley 2016)

According to our results, MAb immunotherapy may be beneficial, although more studies are needed. Broadly speaking, the effects of adjunctive MAb therapy were small. Even though in an open label trial, Tocilizumab showed remarkable improvement in cognition, in a randomized clinical trial there were no effects regarding cognition or negative symptoms. Canakinumab in a randomized clinical trial was beneficial in reducing hsCRP and positive symptomatology, but showed no effects over negative symptoms and cognition. In fact, the outcome that interest the most is improvement of the deficit syndrome, what unfortunately was not seen in all trials. These results may have been due to a limited number of patients or incomplete selection criteria. Only a subgroup of patients show elevation of inflammatory markers which vary depending on the state of the disease. IL-1 and IL-6 are state markers which are decreased during stabilized disease and all selected patients were stable when admitted to all three trials. For this reason, Tocilizumab and Canakinumab are not optimal in such cases, but may be better indicated in acute psychosis. Scientists should administer MAb targeting cytokines according to the state of disease, considering acutely ill or clinically stable patients as two separate clusters in terms of inflammatory markers. Ideally, immunotherapy should be tested in earlier phases of disease, such as in prodromal psychosis and first episode psychosis, because these are related to irreversible grey matter loss which causes cognitive decline.(Bhojraj, Sweeney et al. 2011) Furthermore, all studies were of short duration, what may not be sufficient to capture improvements.

For the future and even for ongoing trials judicious choice of therapeutic target, patient selection, timing of drug administration and duration of therapy are required.(Miller and Buckley 2016) Moreover, evidence suggests that there are other possible targets for MAb therapy, beyond cytokines. In treatment resistant schizophrenia, synaptic pathways are abnormal and evidence suggests that the endogenous ErbB receptors might play an aetiological role. Intrathecal Trastuzumab, a MAb targeting ErbB2 (HER2)(Sastry and Sita Ratna 2004) and Anti-ErbB3 MAb(Li and Yang 2012)

are possible options targeting these. CONFLICT OF INTEREST

The authors declare no conflicts of interest. FUNDING AND DISCLOSURES

CONTRIBUTIONS

Carlos Chaves managed the first literature search and wrote the first draft of the manuscript. Maria A. Vieira-Coelho replicated the literature search, evaluated and added useful information. Both authors contributed to, commented and approved the final version.

VITAE

Dr. Maria Augusta Vieira-Coelho, MD, concluded her Medical studies in 1992 and has a PhD course in Medicine, both in the Faculty of Medicine, University of Porto. Specialized in Psychiatry, currently teaches in the same faculty as Associated Professor. As a scientist, Dr. Maria Coelho has published more than 150 articles.

Mr. Carlos Chaves was born in Porto in 1996. In 2020, he concludes his Master Degree in Medicine in the Faculty of Medicine, University of Porto.

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Gruber, L., T. Bunse, E. Weidinger, H. Reichard and N. Muller (2014). "Adjunctive recombinant human interferon gamma-1b for treatment-resistant schizophrenia in 2 patients." J Clin Psychiatry 75(11): 1266-1267.

Inglese, M. and M. Petracca (2015). "Therapeutic strategies in multiple sclerosis: a focus on neuroprotection and repair and relevance to schizophrenia." Schizophr Res 161(1): 94-101.

Kay, S. R., A. Fiszbein and L. A. Opler (1987). "The positive and negative syndrome scale (PANSS) for schizophrenia." Schizophr Bull 13(2): 261-276.

Keefe, R. S., T. E. Goldberg, P. D. Harvey, J. M. Gold, M. P. Poe and L. Coughenour (2004). "The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery." Schizophr Res 68(2-3): 283-297.

Khandaker, G. M., R. Dantzer and P. B. Jones (2017). "Immunopsychiatry: important facts." Psychol Med 47(13): 2229-2237.

Kirkpatrick, B. and B. J. Miller (2013). "Inflammation and schizophrenia." Schizophr Bull 39(6): 1174-1179.

Knight, J. G., D. B. Menkes, J. Highton and D. D. Adams (2007). "Rationale for a trial of immunosuppressive therapy in acute schizophrenia." Mol Psychiatry 12(5): 424-431.

Kroken, R. A., I. E. Sommer, V. M. Steen, I. Dieset and E. Johnsen (2018). "Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics." Front Psychiatry 9: 753.

Laan, W., D. E. Grobbee, J. P. Selten, C. J. Heijnen, R. S. Kahn and H. Burger (2010). "Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial." J Clin Psychiatry 71(5): 520-527.

Leboyer, M., J. Oliveira, R. Tamouza and L. Groc (2016). "Is it time for immunopsychiatry in psychotic disorders?" Psychopharmacology (Berl) 233(9): 1651-1660.

Leucht, S., C. Corves, D. Arbter, R. R. Engel, C. Li and J. M. Davis (2009). "Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis." Lancet 373(9657): 31-41.

Li, N. and Y. Yang (2012). "Therapeutic use of an anti-ErbB3 monoclonal antibody." Hybridoma (Larchmt) 31(3): 149-154.

Mehta, D., C. L. Raison, B. J. Woolwine, E. Haroon, E. B. Binder, A. H. Miller and J. C. Felger (2013).

"Transcriptional signatures related to glucose and lipid metabolism predict treatment response to the tumor necrosis factor antagonist infliximab in patients with treatment-resistant depression." Brain Behav Immun 31: 205-215. Miller, B. J., P. Buckley, W. Seabolt, A. Mellor and B. Kirkpatrick (2011). "Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects." Biol Psychiatry 70(7): 663-671.

Miller, B. J. and P. F. Buckley (2016). "The Case for Adjunctive Monoclonal Antibody Immunotherapy in Schizophrenia." Psychiatr Clin North Am 39(2): 187-198.

Miller, B. J., J. K. Dias, H. P. Lemos and P. F. Buckley (2016). "An open-label, pilot trial of adjunctive tocilizumab in schizophrenia." J Clin Psychiatry 77(2): 275-276.

Miller, B. J. and D. R. Goldsmith (2017). "Towards an Immunophenotype of Schizophrenia: Progress, Potential Mechanisms, and Future Directions." Neuropsychopharmacology 42(1): 299-317.

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Miyaoka, T., R. Wake, S. Hashioka, M. Hayashida, A. Oh-Nishi, I. A. Azis, M. Izuhara, K. Tsuchie, T. Araki, R. Arauchi, R. A. Abdullah and J. Horiguchi (2017). "Remission of Psychosis in Treatment-Resistant Schizophrenia following Bone Marrow Transplantation: A Case Report." Front Psychiatry 8: 174.

Mizuno, Y., R. A. McCutcheon, S. P. Brugger and O. D. Howes (2019). "Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis." Neuropsychopharmacology. Muller, N. (2018). "Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations." Schizophr Bull 44(5): 973-982.

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Sommer, I. E., D. W. van Bekkum, H. Klein, R. Yolken, L. de Witte and G. Talamo (2015). "Severe chronic psychosis after allogeneic SCT from a schizophrenic sibling." Bone Marrow Transplant 50(1): 153-154.

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Wank, R. (2002). "Schizophrenia and other mental disorders require long-term adoptive immunotherapy." Med Hypotheses 59(2): 154-158.

Weickert T., e. a. (2019). "Reduction in Peripheral C-Reactive Protein Levels with Canakinumab Administration is Related to Reduce Positive Symptom Severity in Patients with Schizophrenia and Inflammation." SIRS 2019 Abstracts: S318.

APPENDICES

Table 1. General trials characteristics and general quality assessment according to Jadad Scale. (Ongoing trials are shaded)

Reference Country Sample size Mean age duration Intervention Study targeted/Target Cytokine outcome Primary

Beneficial effects of

intervention Randomized blinding Double Jadad Scale

Miller et al.

2016 USA 6 35 8 weeks Tocilizumab IL-6 Effect on PANSS, BACS and inflammatory markers Cognition improvement No No 1 Girgis et al.

2017 USA 36 42 12 weeks Tocilizumab vs Placebo IL-6 Effect on PANSS None Yes Yes 4 Weickert et

al. 2019 USA 27 - 8 weeks Canakinumab vs. Placebo IL-1β Effect on PANSS and inflammatory markers Positive symptoms and blood hsCRP levels reduction Yes Yes 3 CATS study Australia 30 - 4 months Canakinumab

vs. Placebo IL-1β Effect on PANSS - Yes Yes 3 NCT02796859 USA 30 - 9 weeks Siltuximab vs.

Placebo IL-6 Effect on BACS - Yes Yes 3 NCT02874573 USA 20 - 12 weeks Tocilizumab vs.

Placebo IL-6 Effect on BACS - Yes Yes 3 NCT03093064 UK 60 - 2 weeks Natalizumab vs.

Placebo α4 integrin Effect on TSPO availability - Yes Yes 3 NCT03194815 UK 80 - 18 months Intravenous immunoglobulin and Rituximab vs. Placebo CD-20 Time to start remission (PANSS ≤ 3 sustained for 6 months) - Yes Yes 3

NCT03818516 USA 20 - 10 days Infliximab vs.

Placebo TNF-α Mean change in reward circuitry connectivity

- Yes Yes 3 NCT03983018 Sweden 12 - 20 weeks Rituximab CD-20 Effect on

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SCHIZOPHRENIA RESEARCH

An International Multidisciplinary Journal of the Schizophrenia International Research Society

AUTHOR INFORMATION PACK

TABLE OF CONTENTS

XXX

• Description

• Audience

• Impact Factor

• Abstracting and Indexing

• Editorial Board

• Guide for Authors

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DESCRIPTION

As official journal of the Schizophrenia International Research Society (SIRS) Schizophrenia Research is THE journal of choice for international researchers and clinicians to share their work with the global

schizophrenia research community. More than 6000 institutes have online or print (or both) access

to this journal - the largest specialist journal in the field, with the largest readership!

Schizophrenia Research's time to first decision is as fast as 6 weeks and its publishing speed is as fast as 4 weeks until online publication (corrected proof/Article in Press) after acceptance and 14 weeks from acceptance until publication in a printed issue.

The journal publishes novel papers that really contribute to understanding the biology and

treatment of schizophrenic disorders; Schizophrenia Research brings together biological, clinical

and psychological research in order to stimulate the synthesis of findings from all disciplines involved in improving patient outcomes in schizophrenia.

AUDIENCE

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Psychiatrists, Neurologists, Pharmacologists, Psychologists.

IMPACT FACTOR

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2018: 4.569 © Clarivate Analytics Journal Citation Reports 2019

ABSTRACTING AND INDEXING

.

Current Contents - Life Sciences Current Contents - Clinical Medicine Embase

PsycINFO PsycALERT PubMed/Medline Scopus

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. DeLisi, Harvard Medical School, VA Boston Healthcare System, 940 Belmont Ave., Brockton, Massachusetts 02301, United States

Deputy Editors

Paola Dazzan, London, United Kingdom

Godfrey Pearlson, West Haven, Connecticut, United States Sophia Vinogradov, San Francisco, California, United States

Associate Editors

Jeffrey R. Bishop, Minneapolis, Minnesota, United States Paulo Lizano, Boston, Massachusetts, United States Urvakhsh Mehta, Bangalore, India

Konasale M. Prasad, Pittsburgh, Pennsylvania, United States

Digital Psychiatry Editor

John Torous, Boston, Massachusetts, United States

Editorial Board

J. Addington, Calgary, Alberta, Canada

A. Anticevic, New Haven, Connecticut, United States D. L. Braff, La Jolla, California, United States

P. Buckley, Augusta, Georgia, United States K. Cadenhead, La Jolla, California, United States E.Y-H. Chen, Pokfulam, Hong Kong

C.U. Correll, Glen Oaks, New York, United States M. Davidson, Tel Aviv, Israel

M. De Hert, Kortenberg, Belgium K.Q. Do, Lausanne, Switzerland R. Emsley, Observatory, South Africa

J. M. Ford, San Francisco, California, United States R. Freedman, Denver, Colorado, United States D. Goff, Boston, Massachusetts, United States A. Grace, Pittsburgh, Pennsylvania, United States M.F. Green, Los Angeles, California, United States R.E. Gur, Philadelphia, Pennsylvania, United States M.-H. Hall, Belmont, Massachusetts, United States P.J. Harrison, Oxford, United Kingdom

P.D. Harvey, Miami, Florida, United States S. Heckers, Nashville, Tennessee, United States D.C. Javitt, New York, New York, United States R.S. Kahn, New York, New York, United States S. Kapur, Melbourne, Victoria, Australia

R. Keefe, Durham, North Carolina, United States S. Leucht, Munich, Germany

K.E. Lewandowski, Belmont, Massachusetts, United States D. A. Lewis, Pittsburgh, Pennsylvania, United States

J. A. Lieberman, New York, New York, United States D. Malaspina, New York, New York, United States A. Malhotra, Glen Oaks, New York, United States S.R. Marder, Los Angeles, California, United States D. H. Mathalon, San Francisco, California, United States R. McCullumsmith, Cincinnati, Ohio, United States P.D. McGorry, Parkville, Australia

J.J. McGrath, Wacol, Queensland, Australia P. McGuire, London, United Kingdom

K.T. Mueser, Boston, Massachusetts, United States R.M. Murray, London, United Kingdom

J.J. van Os, Maastricht, The Netherlands C. Pantelis, Saint Albans, Australia S. Park, Nashville, Tennessee, USA

AUTHOR INFORMATION PACK 19 Mar 2020 www.elsevier.com/locate/schres 3 A. Sawa, Baltimore, Maryland, United States

S.G. Schwab, Nedlands, Western Australia, Australia M.E. Shenton, Boston, Massachusetts, United States T. Si, Beijing, China

V. Srihari, New Haven, Connecticut, United States M. Takeda, Suita, Japan

C.A. Tamminga, Dallas, Texas, United States R. Tandon, Kalamazoo, Michigan, United States H. Verdoux, Bordeaux, France

A. Vita, Brescia, Italy

J.L. Waddington, Dublin, Ireland

C.S. Weickert, Sydney, New South Wales, Australia D.R. Weinberger, Baltimore, Maryland, United States T. Wykes, London, United Kingdom

A. Yung, Parkville, Australia

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GUIDE FOR AUTHORS

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Types of papers:

(1) Full-length papers: 4000 words (excluding tables, figures and references). (2) Review articles upto 5000 words.(3) Letters to the Editors: 600-800 words, 10 references, 1 figure or table.(4) Special solicited research and/or reviews.(5) Invited comments or hypotheses( Less than 1000 words).(6) Editorials.(7) Schizophrenia meeting reviews; solicited and/or submitted.(8) Book reviews.

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