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+{"file": "ukeme0607_NBK545707/s4.nxml", "text": "Limitations\nThere are number of potential limitations of the BeneMin study. The aim of the study was to determine whether or not minocycline protects against the development of negative symptoms over 1 year. The design involved a compromise between, on the one hand, early neuroprotective treatment when a putative neuropathic process might be most active and, on other hand, allowing sufficient time for the process to produce negative symptoms. We chose 1 year based on our previous experience and the evidence that observable changes in brain structure occur over 1 year in first-episode psychosis. However, recent evidence from longitudinal studies in first-episode psychosis challenges our premise that a 1-year follow-up would be sufficient; this indicates that negative symptoms reduce as positive symptoms stabilise and remain low and stable for up to 2 years in those remaining in services and treatment.50 The mean initial negative score of about 17 stabilising at 15 after 1 year in the BeneMin study is very similar to the profile reported by Mezquida et al.50 The present baseline score of 17 is appreciably lower than that of 22 in the Pakistan study,2 and this may have diminished the possibility of finding a protective effect of minocycline. Indeed, the greatest predictor of follow-up in BeneMin was the baseline PANSS negative score, suggesting that influences on negative symptoms had already operated prior to the minocycline trial.\nThe trial had a high dropout rate, but this was mainly as a result of participant choice and was clearly not different between the two groups. Similarly, poor treatment adherence in one or other group is a potential source of bias, but there was no group difference in self-rated attitude to trial medication. Furthermore, sensitivity analysis (see Appendix 2) found that treatment effects were not modified by poor compliance and loss to follow-up. Poor adherence as well as dropout will have reduced exposure to active treatment and thus lessened the power of the study to detect an effect on negative symptoms. However, exploratory analyses found no evidence of trends to efficacy compared with placebo in treatment-adherent individuals or in those with detectable minocycline in plasma at 6 or 12 months.\nPoor training or reliability between raters is a potential explanation for a false-negative study. In BeneMin, extensive training and discussions of ratings continued throughout the trial. A single RA recruited and tested the bulk of participants in each centre because staff turnover was gratifyingly low. This would tend to increase consistency. Agreement among the seven principal RAs of negative scores in up to 11 reference-video SCI-PANSS interviews produced an intraclass correlation of 0.7. Centre was included as a factor in estimating all treatment effects, but none was statistically significant. Furthermore, there were no effects of treatment in any centre when considered separately. Because treatment effects do not vary between centres, it seems unlikely that beneficial effects of minocycline were obscured by a marked deviation in rating or by other unknown systematic deviations in some centres.\nThe lack of effect of minocycline is backed up by the lack of effect on secondary measures that are known to relate to negative symptoms, some of which do not involve external raters; the CDSS and the SFS are self-rated, and the latter has objective measures, such as being in employment. Performance on cognitive function tasks is a known correlate of negative symptoms but was unaffected by minocycline. The secondary measures changed very little over the course of the study year, as might be expected had a continuing neuropathic process been active early in psychosis.\nEfficacy of minocycline in relation to other studies\nThere is no evidence from the BeneMin study that minocycline has important effects on the course of early schizophrenia, in particular on negative symptoms. This study followed the design used in a previous two-centre placebo-controlled RCT conducted by Chaudhry et al.,2 in which minocycline improved negative symptoms when added to treatment as usual for 1 year. In the major centre in Pakistan (70 completers), only negative symptoms improved compared with placebo, by about 3 points on the negative scale. In the Brazilian centre in 24 participants, negative symptoms improved by 8 points more than in those receiving placebo, with similar large improvements in positive subscale and total scores. None of eight other trials of minocycline in the meta-analysis of Xiang et al.51 reported benefits on positive symptoms. There are many possible reasons for the discrepancy between the current findings and the Chaudhry trial results concerning psychosocial, aetiological and therapeutic differences between countries. For example, inflammatory mechanisms might plausibly be more prevalent in Pakistan and therefore be amenable to minocycline\u2019s anti-inflammatory actions. Although there was no evidence for the existence of an \u2018inflammatory\u2019 subgroup of participants with marked responses to minocycline in the Pakistan study, four participants in Brazil did have large responses. The magnitude of the difference between BeneMin and the Pakistan trial is small and may simply reflect chance variation.\nTwo other studies3,52 have reported effectiveness of minocycline in early psychosis. A study by Liu et al.52 would appear to be an outlier given the large and widening 14-point difference on the Scale for the Assessment of Negative Symptoms (SANS) ratings compared with placebo at 10 weeks after treatment (see meta-analysis of Xiang et al.51). Lefkovitz et al.3 reported the emergence of negative symptoms 17 weeks after an acute episode in their placebo-treated group, which did not occur in those randomised to minocycline throughout the episode. These effects on SANS ratings were not apparent on PANSS ratings, in keeping with the present study. In summary, critical examination of the limited previous literature offers little support for substantial effects of minocycline on negative or positive symptoms early in psychosis.\nIt is possible that inflammation is a mechanism relevant to the pathogenesis of severe negative symptoms and cognitive impairment in chronicity and the \u2018deficit syndrome\u201953 or in treatment resistance. An early case study54 reported dramatic improvement in two patients with catatonia prescribed minocycline as an antibiotic for pneumonia, and this was followed by a 4-week open-label study5 in 22 patients with resistant illnesses and high positive and negative PANSS scores, all of which improved after minocycline. A number of other case reports have reported improvement in negative symptoms55\u201358 following the addition of minocycline. However, only two double-blind RCTs in established schizophrenia have been published. A study59 in patients partially responding to clozapine reported no effect on negative symptoms (the primary outcome variable) rated from the Brief Psychiatric Rating Scale (BPRS), but some differences in other BPRS scores were reported, with improvement in cognitive performance. A study from Iran60 reported very large benefits on negative symptoms in patients with chronic illnesses.\nMechanistic markers\nThe most direct evidence for neuroinflammation in early schizophrenia has come from PET imaging of microglial activation. Various radioligands have been developed that have affinity for the 18-kDa translocator protein (TSPO) in the mitochondria of activated microglia in order to image neuroinflammation. Two early studies in schizophrenia reported increased 11C-PK11195 binding in small groups of 10 and 7 patients compared with controls.20,61 However, seven later studies in larger samples using PK11195 and more recently developed ligands did not report increases; this includes four studies in recent-onset schizophrenia.62\u201365 Only two studies have studied drug-naive patients on antipsychotic medication. Holmes et al.62 found no increases in PK11195 binding in untreated first-episode patients but increases in those on risperidone. There were no relationships with circulating hsCRP concentrations. Collste et al.65 found markedly reduced 11C-PBR28 binding in several brain regions in drug-naive recently diagnosed patients. One recent study66 stands out as it reported increases in 11C-PBR28 binding in both people at ultra-high risk and those in a first episode. The findings are controversial because when analysed using conventional modelling (without co-varying whole-brain binding), no increases in radioligand binding were seen. Further studies are under way but, because several reasonably powered studies have found no increases in TSPO binding in recent-onset schizophrenia, it is questionable whether microglial activation occurs. This in turn suggests that the lack of effect of minocycline in the BeneMin study may reflect an absence of neuroinflammation in recent-onset schizophrenia.\nPeripheral circulating cytokine concentrations were not markedly increased compared with norms in the study laboratory, but in the absence of a control group we cannot exclude a group effect. We found no evidence in exploratory analyses that those with above median baseline hsCRP or IL-6 concentrations showed a greater effect of minocycline than those with below median levels on PANSS subscales or on CDSS ratings. Minocycline had no overall effect on hsCRP or IL-6 concentrations. Remarkably, in view of the widespread use of minocycline as an anti-inflammatory drug, only one report of minocycline effects on circulating cytokines was found in PubMed searches. In a study67 in patients with rheumatoid arthritis, IL-6 concentrations decreased over 6 months in the minocycline treatment group but not in the placebo group, but whether or not the group difference was statistically significant was not clear; hsCRP decreases correlated with IL-6 decreases in the minocycline group. A recent meta-analysis68 found no evidence that APD treatment moderated the increase in hsCRP associated with the diagnosis of schizophrenia. It would therefore appear that the lack of effect of minocycline on cytokines in the BeneMin study may be further evidence of a lack of peripheral inflammation in the BeneMin participants.\nPrevious evidence, including from BeneMin investigators, reported raised IL-6 and interferon gamma in patients measured within days of first presentation and in those who did not respond 3 months later.69 Few of the BeneMin sample would be non-responders judging by the mild to moderate range of total PANSS scores. However, cytokine concentrations in the 21 participants with greatest baseline PANSS total scores (84\u2013118) did not differ from the remaining 180. Nevertheless, the possibility remains that peripheral inflammation occurs during acute-phase psychosis and in association with treatment resistance, and that anti-inflammatory drugs such as minocycline might benefit participants in these subgroups with clear biomarker evidence of central nervous system or systemic inflammation.\nMinocycline has many properties apart from its anti-inflammatory actions that should promote cell survival, such as the antioxidant, antiapoptotic, blockade of glutamate neurotoxicity and mitochondrial damage, which has been reviewed in two studies.17,70 Indeed, these properties were the rationale for the minocycline study: to trial a neuroprotective agent in early schizophrenia. So far, however, minocycline\u2019s neuroprotective properties in preclinical assays have not been translated into clinical efficacy. It is clearly not effective in motor neurone disease10 or multisystem atrophy.71 A possible benefit in slowing progression of multiple sclerosis has been reported after 6 months but not 12 months of treatment.72 There are equivocal findings in a few case reports and in pilot studies in Parkinson\u2019s disease,71 stroke8,73 and fragile X syndrome.74 In the BeneMin study there was no statistically significant loss of medial prefrontal GMV over the course of the study year and, therefore, no detectable neuropathic process for minocycline to exert a neuroprotective effect. In the Brazilian arm (n\u2009=\u200930) of the Chaudhry et al.2 trial, Chaves et al.75 carried out structural MRI (1.5\u2009T) scans at the 12-month assessment. The placebo group showed localised reductions in GMV in the left motor cortex (BA6) and the left mid-posterior cingulate cortex (BA24) compared with the minocycline group. In the absence of baseline scans it is not possible to know if loss of GMV occurred in the placebo group and, therefore, whether or not the difference at 12 months represents a possible localised neuroprotective effect of minocycline. In the BeneMin structural MRI scans, there were no effects of minocycline in any region in an exploratory whole-brain analysis.\nAny suggestion that the present study missed microglial activation because PET TSPO binding does not detect it or that minocycline is ineffective against it would be premature in the light of recent studies in depression. Two studies76,77 reported increased PET TSPO binding in patients with major depressive disorder, and a further two studies78,79 reported that minocycline substantially reduced depression in treatment-resistant patients78 and in a sample of patients with bipolar depression.79 This suggests that fundamental differences may exist between the immune basis of psychosis and that of depression.\nImplications for research\nThe BeneMin study, taken together with the existing literature, suggests that up to 12 months of treatment with minocycline does not improve the symptomatic or functional status of people within 5 years of a diagnosis of schizophrenia. Furthermore, we found little evidence of persisting neurodegeneration or systemic inflammation that the known actions of minocycline could target. It is possible that such processes occur in acute-phase schizophrenia or in treatment-resistant subgroups. However, much firmer biomarker evidence of these pathological processes would seem necessary before further trials of minocycline are carried out in psychosis.\nWe suggest some priorities for future research as follows:\nSearch for other immune mechanisms in psychosis including T-cell-mediated autoimmune processes that act via neuromodulation rather than neurodegeneration.\nFind better radioligands for PET imaging of microglia and other inflammatory cells in the brain, including astroglia.\nUse novel trial designs to detect the benefit of monoclonal antibodies and other immune suppressants in acute or treatment-resistant illnesses. This approach is encouraged by unpublished evidence (Professor IB Chaudhry, University of Manchester and Pakistan Institute of Living and Learning, 2016, personal communication) from a clinical trial80 that low-dose methotrexate has unexpected antipsychotic effects.", "pairs": [], "interleaved": []}
+{"file": "ukeme0607_NBK545707/ack1.nxml", "text": "Participants and others\nThe BeneMin study team members are Kelly Byrne, Emma Eliasson, Catherine George, Annalisa Giordano, Carl Krynicki, Fara Lunat, Sarndip Sangha, Andrew Watson and Naghmeh Nikkheslat.\nWe acknowledge the outstanding generosity of time and co-operation of the service users who consented to take part in the study with the attendant inconvenience of taking medication for 1 year and undergoing brain scans and many interviews and tests. We also thank all the carers for their co-operation and support.\nStephen Hopkins (Reader Retired, Heathcare Science, Salford Royal Hospital) was a co-applicant and designed and supervised the collection and storage of samples for cytokines.\nThe study could not have been completed without the co-operation of many NHS and university staff and we acknowledge them below.\nLocal PIs: Jonathan Hellewell, Tirthankar Mukherjee, Andrew Boardman, Sonia Johnson, Nikola Rahaman, Ilyas Mirza and Remy McConvey.\nResearch and innovation staff and pharmacists at the following mental health NHS and foundation trusts:\nManchester Mental Health and Social Care NHS Trust\nGreater Manchester West Mental Health NHS Foundation Trust\nCheshire and Wirral Partnership NHS Foundation Trust\nLancashire Care NHS Foundation Trust\nPennine Care NHS Foundation Trust\nBirmingham and Solihull Mental Health NHS Foundation Trust\nCamden and Islington NHS Foundation Trust\nCentral and North West London NHS Foundation Trust\nWest London Mental Health NHS Trust\nBarnet, Enfield and Haringey Mental Health NHS Trust\nSouth London and Maudsley NHS Foundation Trust\nCambridgeshire and Peterborough NHS Foundation Trust\nLancashire Care NHS Foundation Trust\nRoyal Edinburgh Hospital, NHS Lothian\nLynebank Hospital, NHS Fife.\nOpenCDMS managers John Ainsworth, Matthew Machin and especially Kathleen Haigh-Hutchinson for their patience in maintaining the database after its official close-down.\nClinical Research Network staff led by Angie Parker and Moira Winters.\nData Monitoring and Ethics Committee chairperson Stephen Cooper (University of Belfast) and members Carol Gamble (University of Liverpool), Peter Liddle (University of Nottingham) and Graham Dunn (University of Manchester).\nTrial Steering Committee: chairperson John Geddes (University of Oxford), Robin Jacoby (University of Oxford), Max Birchwood (University of Birmingham) and Gerald Wright (service user representative).\nContributions of authors\nBill Deakin (Professor, Psychiatry) was the chief investigator and wrote the manuscript.\nJohn Suckling (Professor, MR physicist) was a co-applicant and designed and supervised the imaging component of the study.\nPaola Dazzan (Professor, Psychiatry) was a co-applicant and designed and supervised the cytokine investigations of the study.\nEileen Joyce (Professor, Psychiatry) was a co-applicant and designed and supervised the neuropsychological component of the study.\nStephen M Lawrie (Professor, Psychiatry and Neuro-imaging) was a co-applicant. He was involved in the design of the study and recruitment.\nRachel Upthegrove (Senior Clinical Lecturer, Psychiatry) wa a co-applicant. She was involved in the development of recruitment at Birmingham.\nNusrat Husain (Professor, Psychiatry) was a co-applicant. He was involved in the design of the study and overall recruitment strategy.\nImran B Chaudhry (Professor, Psychiatry) was a co-applicant. He was involved in the design of the study and overall recruitment strategy.\nGraham Dunn (Professor, Statistics) was a co-applicant. He supervised the statistical design of the study and the analysis.\nPeter B Jones (Professor, Psychiatry) was a co-applicant. He was involved in the design of the study.\nDanuta Lisiecka-Ford (Post-doctoral Research Assistant) managed the MRI in the five scanners.\nSh\u00f4n Lewis (Professor, Psychiatry) was a co-applicant. He was involved in the design of the study.\nThomas RE Barnes (Professor, Psychiatry) was a co-applicant. He designed and supervised the assessment of neurological and other side effects of medication.\nSteven CR Williams (Professor, Imaging Sciences) was a co-applicant. He contributed to the design of the imaging component of the study.\nCarmine M Pariante (Professor, Perinatal Psychiatry) supervised the hsCRP and cytokine assays.\nEmma Knox (Trial Manager) was involved in the design of the study, and in all aspects of the study\u2019s management and monitoring.\nRichard J Drake (Reader, Psychiatry) was involved in the design of the study and supervised PANSS training and other clinical assessments.\nRichard Smallman (Post-doctoral Research Associate) was involved in study set-up and data management.\nNicholas M Barnes (Professor, Neuropharmacology) supervised the minocycline assays.\nAll authors reviewed, revised and approved the final version of the manuscript.\nSupport\nJohn Suckling received additional support from the Cambridge NIHR Biomedical Research Centre, the Behavioural and Clinical Neuroscience Institute, University of Cambridge, and grants from the Cambridgeshire and Peterborough NHS Trust Research Strategy Committee.\nBill Deakin contributed additional funding from his NIHR Senior Investigator award for salaries to support the study for Richard Smallman and Amy Bland (who helped with the project set-up) and to purchase the initial batch of minocycline, an extra treatment cost. All 11 NHS trusts with the exception of South London and Maudsley NHS Trust contributed their share of extra treatment costs.\nAdditional support for hsCRP and cytokine assays performed by Post-doctoral Research Fellow Naghmeh Nikkheslat was provided by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King\u2019s College London.\nPublications\nLisiecka DM, Suckling J, Barnes TR, Chaudhry IB, Dazzan P, Husain N, et al. The benefit of minocycline on negative symptoms in early-phase psychosis in addition to standard care \u2013 extent and mechanism (BeneMin): study protocol for a randomised controlled trial. Trials 2015;16:71.\nDeakin B, Suckling J, Barnes TR, Byrne K, Chaudhry IB, Dazzan P, et al. The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial. Lancet Psychiatry 2018;5:885\u201394. [Erratum published in Lancet Psychiatry 2018;5:e28].\nData-sharing statement\nData are archived at the University of Manchester. All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.\nPatient data\nThis work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people\u2019s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone\u2019s privacy, and it\u2019s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: (https://understandingpatientdata.org.uk/data-citation).\nDisclaimers\nThis report presents independent research. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the MRC, NETSCC, the EME programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the EME programme or the Department of Health and Social Care.", "pairs": [], "interleaved": []}
+{"file": "ukeme0607_NBK545707/s1.nxml", "text": "Negative symptoms of schizophrenia\nPatients with chronic schizophrenia have an impaired quality of life, experiencing social isolation, self-neglect, unemployment and reduced activities of daily living, despite current treatments. Symptoms are broadly grouped into positive and negative. The negative symptoms reflect the absence or diminution of normal behaviours and functions, and include emotional and social withdrawal, anhedonia, lack of drive and deficiencies in emotional responsiveness. Negative symptoms persist and, along with cognitive impairment and the duration of untreated psychosis (DUP), they fairly consistently relate to impaired social functioning.1 Findings such as the correlation between DUP and negative symptoms suggest that active psychosis may reflect a neuropathic process that results in negative symptoms and thus in impaired quality of life. This has led to interest in directly targeting neuroprotection in early treatment to prevent the development of or alleviate negative symptoms and cognitive decline and thus improve social function and quality of life. Although positive and disorganised symptoms usually respond to drug treatment, no antipsychotic drug (APD) treatment is unequivocally effective for negative symptoms.\nPrevious studies of minocycline and symptoms of schizophrenia\nThe Stanley Medical Research Institute funded two double-blind, randomised, placebo-controlled studies2,3 of the putative neuroprotective agent minocycline for the negative symptoms of schizophrenia. A two-centre study in Brazil and Pakistan2,4 was supervised by the University of Manchester. A total of 94 people with schizophrenia who were on stable medication completed 12 months of add-on treatment with placebo or minocycline. Minocycline-treated patients showed an overall greater improvement in their total Positive and Negative Syndrome Scale (PANSS) score (p\u2009=\u20090.03). This was driven by the improvement in negative syndrome scores (p\u2009=\u20090.007; Cohen\u2019s d\u2009=\u20090.54); the improvement in positive symptom ratings was smaller and only trend significant (p\u2009=\u20090.06). In a subset of patients, ratings made at 6 months were available, and treatment effects were apparent at that time. These data also suggest that improvement in negative symptoms continues to 12 months but that improvement in positive symptoms is maximal at 6 months. Although improvement in positive symptoms was small overall, it was very marked in four patients in the Brazil arm of the study, suggesting that the effect of minocycline may be significantly heterogeneous. A marked acute antipsychotic effect of minocycline has been reported in treatment-resistant patients.5 A second randomised controlled trial (RCT) was carried out in Tel Aviv3 in 70 relapsed patients. After stabilisation on a second-generation APD, the patients were randomised to placebo or minocycline in a 1\u2009:\u20092 ratio. Significant treatment effects on negative but not on positive symptoms were detectable at the first rating at 3 months. No other trials were registered on US or UK databases prior to BeneMin.\nMechanism of action of minocycline: anti-inflammatory and neuroprotective\nMinocycline has been shown to have neuroprotective properties in preclinical models of several neurodegenerative diseases.6,7 Preliminary clinical trials suggested that stroke8 and Parkinson\u2019s disease9 may be helped by minocycline but that amyotrophic lateral sclerosis (ALS) and Huntington\u2019s disease are not.10,11 Neuronal cell numbers are not reduced in post-mortem brain studies in schizophrenia, which points rather to loss of neuronal branching and possible loss of the astroglial and oligodendroglial cells that support neuronal function.12 Furthermore, there is a good case for antecedent developmental abnormalities.13 Nevertheless, subtle loss of grey matter in brain imaging studies certainly occurs, and this continues with transition to psychosis and during the early course of schizophrenia. Lieberman et al.14 reported loss of grey matter in magnetic resonance imaging (MRI) scans in patients treated in their first year of illness, and this was also reported by Cahn et al.15 over 5 years. In the latter study, the brain changes predicted poor functional outcome and DUP predicted the grey matter changes.16 The demonstration that minocycline lessens grey matter loss and its association with improved negative symptoms would galvanise action on neuroprotection as a major therapeutic target in schizophrenia.\nMinocycline has multiple anti-inflammatory and anti-apoptotic properties; for example, it decreases production of cytokines and inducible nitric oxide synthase, and inhibits microglial activation.17 The case for inflammatory mechanisms in schizophrenia had strengthened prior to BeneMin. For example, immune gene variants are associated with psychosis risk, and a meta-analysis18 of many studies of circulating cytokine concentrations had reported medium effect sizes (\u22480.5) for IL-1 receptor antagonist (IL-1RA), IL-2R and IL-6. Some post-mortem brain studies and a recent positron emission tomography (PET) imaging study have reported evidence of microglial activation in schizophrenia.19,20 Although stroke and other neurological disorders are associated with increased circulating cytokines, it remains uncertain whether or not the cytokines originate from the brain. We proposed to use MRI structural sequences that are sensitive to brain inflammation and to determine whether or not group differences relate to circulating cytokines.\nMinocycline, glutamate and schizophrenia\nImpaired N-methyl-d-aspartate (NMDA) glutamate receptor function has long been implicated in the pathogenesis of schizophrenia. Drugs such as phencyclidine and ketamine block NMDA function and reproduce predominantly the negative symptoms of schizophrenia in healthy volunteers.21 They cause dysfunctional glutamate release, which can exert neurotoxic effects.22 Atypical APDs lessen their behavioural effects and, remarkably, so does minocycline.23 Furthermore, we recently found evidence that a single pretreatment of anaesthetised rats with minocycline caused a highly significant block of ketamine\u2019s desynchronising effects on cortical electrophysiology (Professor J Gigg, University of Manchester, 2014, personal communication). Thus, minocycline could improve negative symptoms by reversing a disease-related impairment of NMDA function that may directly underlie negative symptoms or cause them via a toxic effect on neuronal branching or glial support cells. We used cognitive performance, in the absence of a measure of glutamate function, to detect a pharmacological action rather than, or in addition to, neuroprotective effects. We aimed to determine whether the benefits of minocycline on negative symptoms were direct or were mediated by an improvement in cognitive processes, as reflected by functional magnetic resonance imaging (fMRI) during the N-back working memory task.\nRationale for the BeneMin study\nThe rationale of the study was to use proven scientific infrastructure to:\nconduct a multisite, double-blind, RCT to evaluate the effectiveness of minocycline in addition to standard care, compared with standard care alone, in preventing the development or worsening of negative symptoms of schizophrenia over 1 year if given early in the course of the illness\nunderstand how minocycline works.\nThe study built on the demonstrated proof of concept of the efficacy of minocycline on negative symptoms in two placebo-controlled clinical trials24,25 in patients on stable APD treatment. Minocycline also lessened weight gain in both RCTs and was well tolerated, with a good safety profile. The study aimed to evaluate how rapidly minocycline works on negative symptoms in early (first 5 treated years) psychosis and whether or not it is effective in reducing positive symptom; there are no placebo-controlled trials in acute psychosis. Minocycline could therefore reduce the considerable side effect burden of APDs (e.g. weight gain, diabetes mellitus and hyperlipidaemia) by reducing the dose of APDs necessary to improve psychosis and by lessening drug-induced weight gain. A clinically important health gain was realistic given the effect size of 0.5 on negative symptoms in the two efficacy trials.\nMinocycline has a number of actions that could be relevant to its neuroprotective effects and to its beneficial effects in schizophrenia. Therefore, validated biomarkers of potential disease mechanisms were built into the trial design. The study thus aimed to test an entirely new scientific and clinical principle in the treatment of psychosis, with broader implications for our understanding of the relationship between brain changes, cognitive function and negative symptoms.\nMost of the principal investigators collaborated on the Medical Research Council-funded PsyGrid e-science project. PsyGrid constructed an information systems platform, recruited 960 first-episode psychosis patients in 2 years and collected longitudinal clinical assessments that have been used in the power calculations for this study. Patients were identified by research assistants (RAs) based in eight collaborating centres of the Mental Health Research Network. The CSOs carried out assessments and transferred anonymised data via their local computer portal of the Open Clinical Data Management System (OpenCDMS) secure project management software. The proposed study used the same methods, including randomisation, and trial management functions already deployed in other multisite trials. PsyGrid addressed the ethical and legal issues involved in the secure and confidential research assessment of people in their first episode of psychosis.\nRationale and feasibility of multicentre imaging\nFeasibility study\nLarge numbers of patients are needed to allow detection of subtle biological effects of psychiatric illness and drug action on brain structure and function. Imaging studies conducted across multiple centres offer major opportunities to bring patient recruitment into a manageable time frame. However, there are significant operational and statistical challenges, notably the addition of between-centre variance. To address these issues, the PsyGrid and NeuroPsyGrid25 consortia undertook a longitudinal calibration study in which 12 male volunteers were scanned at five centres under the same study protocol as we propose to use.\nA voxel-based method of calculating statistical power for multicentre imaging studies was derived from these data and has been used as the basis for power calculations herein.24 In addition, functional and structural MRI data were modelled at each brain voxel to estimate the partitioning of variance between the main effects of centre, subject, occasion and within-occasion order, as well as interactions of centre-by-occasion, subject-by-occasion and centre-by-subject.\nBetween-centre variance was limited to around 10% of the total. The main effect of subject was the largest variance partition for structural MRI (70\u201380%), and error (unexplained) variance was the largest for functional MRI (>\u200980%). Moreover, subject-by-centre interactions were generally 1\u20132% of the total variance. Therefore, there are no insurmountable obstacles to using MRI as an outcome variable in multicentre trials, and including a factor for centre in analysis falls within the guidelines of the Steering Committee of the International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, which cover the statistical analysis of magnetic resonance images.\nStructural imaging\nThe loss of grey matter was assessed by computational segmentation of high-resolution T1-weighted images of the brain. As an adjunct to the measurement of cytokines in peripheral blood, a T2-weighted image (along with a proton-density-weighted image as part of a dual-echo sequence) was acquired to observe possible neuroinflammation. Furthermore, in combination with the T1 image, we also used multichannel texture analysis, pioneered in the assessment of multiple sclerosis lesions, to identify areas of abnormal MRI contrast associated with inflammation and to observe potential longitudinal changes.\nFunctional imaging of cognition\nEcho-planar images depicting blood oxygen level dependent (BOLD) contrasts during performance of the N-back working memory task26,27 show engagement of an executive function network comprising the dorsolateral prefrontal cortex, the anterior cingulate cortex and the parietal cortex. Impaired functioning in this system has been strongly implicated in the pathogenesis of schizophrenia for several decades.28 Evidence suggests that underlying deficits in intrinsic NMDA glutamate\u2013gamma-aminobutyric acid (GABA) neurotransmission29 and impaired connectivity between elements of the network30 contribute to the impairment. Performance and fMRI measures in the N-back task should therefore be especially sensitive to any NMDA cognitive-enhancing effects of minocycline, particularly in schizophrenia. BOLD-sensitive data were also acquired while participants were resting (i.e. task absent) in order to investigate the endogenous dynamics and functional connectivity in frontotemporal circuits widely implicated in schizophrenia.30\nObjectives\nResearch questions\nIf minocycline is started early in schizophrenia, does it improve negative symptoms or lessen their development over the next 12 months more than it does in established illnesses, and does this improve quality of life? Does minocycline work by its neuroprotective or anti-inflammatory actions or by its effects on glutamate?\nPrimary and subsidiary effectiveness predictions\nPrediction 1: minocycline minimises later negative symptoms when administered during the acute phase of psychosis, compared with standard care alone.\nPrediction 2: minocycline reduces weight gain and adverse metabolic changes associated with standard antipsychotic treatments.\nPrediction 3: improvements in negative symptoms will translate into improved functioning and quality of life.\nMechanistic hypotheses\nHypothesis 1: minocycline works by lessening a degenerative process that is most active in the acute phase of psychosis and is responsible for the development of negative symptoms. The hypothesis predicts that the loss of grey matter, known to occur during the early years following the onset of psychosis, will be lessened by minocycline treatment and that this will correlate with, and explain, improved negative symptoms.\nHypothesis 2: minocycline works by lessening an inflammatory process in the brain that gives rise to negative symptoms, possibly but not necessarily mediated by subtle neurodegeneration (see hypothesis 1). The hypothesis predicts that circulating proinflammatory cytokines will be lessened by minocycline treatment.\nHypothesis 3: minocycline works by ameliorating defective NMDA glutamate receptor function, which mediates negative symptoms. The hypothesis predicts that minocycline will improve cortical function as measured by fMRI activation during a working memory task and resting state connectivity, and reduce baseline concentrations of glutamate/glutamine, as measured by magnetic resonance spectroscopy. It also predicts that the benefits to negative symptoms wane when the drug is stopped. However, it is possible that glutamate actions could also be neuroprotective (see hypothesis 1) whether or not minocycline enhances glutamate function in the short term.\nSome of the results of the BeneMin study have been published.31", "pairs": [], "interleaved": []}
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