Do antipsychotics inflame the brain?

Lead Research Organisation: King's College London
Department Name: Neuroscience

Abstract

Psychological and neurological brain disorders including schizophrenia, affect approximately 38.2% of the total European Union (EU) population per year, corresponding to 164.7 million persons. The total cost of such disorders in Europe in 2010 was estimated to be 798 billion euros. Multiple hypotheses have been proposed to explain how schizophrenia develops. One hypothesis suggests the immune system of schizophrenia patients is over-active, a process known as inflammation. This process includes activation of microglia, a specific type of immune cell in the brain. Microglia are specialist cells, which can take on many functions, allowing them to shape the immune response. Whilst this is important to maintain the normal state of the brain, if unchecked, microglial activation may ultimately become detrimental, leading to damage and worsening of disease symptoms. Microglia also play a key role in shaping the development of the brain, by regulating the connections between nerve cells and thus the efficient flow of information from one part of the brain to another. Multiple studies have now provided evidence that inflammation and microglial activation are present in the brain of schizophrenia patients, either as a result of genetic mutation or environmental risk factors such as infections during pregnancy, or exposure to stress.

Antipsychotics used to treat schizophrenia and increasingly other psychiatric disoders, are often ineffective, fail to treat social and cognitive symptoms and are associated with adverse side effects. Blocking, or limiting inflammation, using "anti-inflammatory" drugs may therefore represent a novel and effective treatment for some schizophrenia patients. However, many studies have found only modest clinical benefits of such drugs. There is accumulating evidence that antipsychotics themselves are anti-inflammatory; however, this is based on unrepresentative cellular models that don't reflect what happens in the living brain. Furthermore, existing studies in animals have only used single, or non-clinical, doses of antipsychotics. Ethically, we cannot withhold antipsychotic treatment from schizophrenia patients, nor can we prescribe them to healthy individuals to study the effects in humans. It is therefore imperative to develop the evidence in realistic animal models.

Our previous studies, in which we closely match the way antipsychotics are given to patients, have shown that these drugs cause activation of microglial cells in the rat brain. Using the same imaging technology that is used in patients, we have also shown that the areas of the brain where the microglial cells are activated are also shrinking following antipsychotic drug treatment. This is similar to reports that antipsychotics may decrease the volume of the brain in schizophrenia patients (Nature; doi: 10.1038/news.2011.75). However, we do not know if these antipsychotic-induced brain volume changes are "good" or "bad" and if the microglial cells are trying to repair the brain, or are in fact causing the damage. In this proposal, we will answer these very questions using experimental animals, which mimic to some extent the inflammation seen in the brains of schizophrenia patients. We will treat these animals with antipsychotics or a placebo and scan the brains of these animals using the same methods that are used in patients. We will then dissect out the brain tissue to assess the effects of antipsychotics on brain microglia at the cellular and molecular level post-mortem. The results of these experiments will tell us whether antipsychotics are "pro" or "anti" inflammatory and how this relates to brain effects of these drugs, including changes in volume and behaviour. Answering these questions is essential to optimise anti-inflammatory treatment strategies for schizophrenia and clarify concerns over the effects of these drugs on brain volume.

Technical Summary

Antipsychotic drugs have both pro- and anti-inflammatory effects. I have shown that clinically comparable, chronic, antipsychotic drug treatment increases microglial activation in the rat brain. Furthermore, this pattern of microglial activation overlaps topographically with brain regions that decrease in volume in antipsychotic-treated rats. The precise impact of antipsychotics on microglial function and how this relates to drug-induced brain volume changes is however, unknown. Furthermore, we do not have a detailed understanding of how antipsychotics affect the expression of the translocator protein (TSPO), a clinical imaging marker for microglial activation, but also a regulator of microglial activation state.

To address these questions I will expose rats to an immune stimulus (poly(I:C) in gestation, which recapitulates pathological and behavioural deficits relevant to schizophrenia. I will then treat these animals as adults with clinically comparable doses of typical or atypical antipsychotics, or a vehicle control and pursue the following specific aims:

1) I will use a combination of in vivo and ex vivo magnetic resonance imaging, coupled with post-mortem cellular (immunohistochemistry and stereology) and molecular (gene expression from isolated brain microglia) analysis to determine the effects of antipsychotics on microglial activation state and how this relates to brain volume.

2) I will elucidate the effects of antipsychotics on TSPO ligand binding using use post-mortem autoradiography and dissect the cellular origin of this signal and consequences on microglial activation using immunohistochemistry and gene expression analysis in isolated brain microglia.

3) I will measure peripheral inflammation in the blood using multiplex cytokine and correlate these to central microglia activation, MRI and TSPO signals. This will characterise the relationship between peripheral inflammation, central markers of inflammation and brain volume (MRI).

Planned Impact

Antipsychotic drugs, have both pro- and anti-inflammatory effects, but their specific actions on brain microglia are unclear. Parsing this relationship is critical, to guide effective use of these medications, but also appropriate use of adjunct anti-inflammatory treatments. Furthermore, we do not have a detailed understanding of how antipsychotics affect the expression of the translocator protein (TSPO), a clinical imaging marker of microglial activation, but also a critical regulator of microglial activation state. Given the challenges in carrying out studies of these issues in patients, it is critical to develop the initial evidence in animal models, which offer the advantages of differentiating the effects of disease from drug, linking in-vivo whole-brain findings to ex-vivo histopathology. This work will directly and indirectly benefit a number of groups:

1) Clinical and basic researchers: The results will provide clarity on the effects of antipsychotics on neuroimaging signals, particularly for TSPO. Furthermore, our model offers a well-characterized 'preparation' to test and compare antipsychotic effects on inflammation. As newer non-D2 antipsychotics are developed, it will be critical to examine if they are similar or different to the present ones in terms of their effects on microglia. The model can then be used in the future to identify potential add-on strategies, which may avoid potential adverse effects. Clearly our findings in this model can only be used as a basis for a further clinical trial - but, because our approach uses clinic-like doses, drug exposure and clinically comparable measurements, the likelihood of translation is higher.

2) Patient groups and the general public: Schizophrenia is a devastating disorder affecting 1% of population; in the UK alone there in excess of 250,000 diagnosed patients. Schizophrenia is commonly treated with antipsychotic drugs but many patients show insufficient responses to current treatments. In addition, we still have an incomplete understanding on how antipsychotic drugs exert their beneficial or adverse effects. It is therefore critical to conduct detailed explorations of molecular and cellular changes in brains exposed to these medications to address this knowledge gap. Completion of this work will therefore facilitate a thoughtful revaluation of the effects of antipsychotics. This will ensure the optimised used of these medications for the ultimate benefit of patients and their families.

3) Government Agencies: The treatment of schizophrenia in the UK costs an estimated £6.7 billion per annum. To reduce this burden of cost for care, novel and more effective treatments for schizophrenia are required. It is equally essential however, to optimize the use of antipsychotic medications currently used clinically. Both approaches require detailed examinations of the effects of these drugs in the brain at the cellular and molecular level in controlled experimental settings. Therefore, the results of the current study, by providing this information will not only guide future studies aimed at developing novel treatments, but also have the potential to reconfigure how we currently view and use these medicines.

4) Pharmaceutical companies: We still lack a complete understanding of how antipsychotic drugs exert their beneficial or adverse effects, particularly with respect to the immune system. It is therefore critical to conduct detailed explorations of molecular and cellular changes in brains exposed to these medications to address this. The results of the proposed project will address this by pointing to brain effects of established medications on microglia and inflammatory pathways that are not well understood, but which may hold clues to new treatment approaches that may be exploited by pharmaceutical companies.

Publications

10 25 50

publication icon
Mondelli V (2017) Brain microglia in psychiatric disorders in The Lancet Psychiatry

 
Description Industry award
Amount £9,713 (GBP)
Funding ID EPBA1979835-A17 
Organisation F. Hoffmann-La Roche AG 
Sector Private
Country Global
Start 06/2016 
End 09/2016
 
Description International Schizophrenia resarch congress (San Diego, California) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I am organising a workshop at the 16th International Congress for Schizophrenia research entitled "Neuroadaptations to antipsychotic drugs: optimising use of current medication through a deeper understanding of antipsychotic drug action in the brain and body". The workshop will comprise 4 talks from internationally recognised speakers in this field, with a mixture of basic and clinical scientists. There will then be a ~30 minute panel discussion with direct interactions from the audience in a question and answer format. The aim of this workshop is to stimulate discussion on a highly clinically relevant topic. Specifically, we aim to consider and debate how we might use current and evolving knowledge and new methodologies in the fields of neuropharmacology and neuroscience, to advance our understanding of the long-term impact of antipsychotic treatment. Ultimately, this may inform the clinical use of these drugs and pave the way for development of novel treatment strategies or optimized antipsychotic drugs.
Year(s) Of Engagement Activity 2017
 
Description Invited lecture, University of Oulu, Finland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I was invited to give a lecture at the Department of Psychiatry, University of Oulu in Finland on our MRC-funded work concerning the effects of antipsychotic drugs on rodent brain volume. This complemented studies in humans done at Oulu concerning this quesiton, based on data collected from the North Finalnd Birth Cohort (1968). The talk led to discussions afterwards and plans for future work with our colleagues in Oulu.
Year(s) Of Engagement Activity 2019
 
Description Invited seminar at School of Pharmacy, Manchester University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Approximately ~40 people from the School of Pharmacy attended a seminar given by myself including a description of my research into the effects of antipsychotic drugs on brain volume and the interactions with the immune system, funded by the MRC. The session provoked a lenthgy series of questions and there were several independent meetings with principle investigators in the School thereafter to discuss possible future and ongoing research collaborations.
Year(s) Of Engagement Activity 2017
 
Description Invited seminar presentation at Centre for Addiction and Mental Health, Toronto, Canada 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I gave 2 seminars on our MRC funded work concerning the effects of antipsychotic drug exposure on the immune system and brain volume in rodent models at CAMH in Toronto as part of thier Schizophrenia and Neuroimaging grand rounds respectively. The audience was composed of physicians, clinician scientists and UG/PG students. Both talks sparked debtate and questions and led to plans for future collaborative research.
Year(s) Of Engagement Activity 2019
 
Description Invited seminar presentation, University of Newcastle 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I was invited to give a talk on our MRC-funded research examining the differential imapct of antipsychotics and mood stabilisers on rodent brain volume using MRI and synaptic density as assessed using PET and post-mortem follow up. The talk led to a discussion for future directions of this work and plans were made to continue working on lithium with colleagues in Newcastle (Dr David Cousins).
Year(s) Of Engagement Activity 2019
 
Description Invited seminar presentation, Wellcome Centre for Integrative Neuroimaging, University of Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I participated as an invited speaker at a workshop held to illustrate the potential of small animal MR imaging at the Wellcome Centre for Integrative Neuroimaging, University of Oxford. I gave two talks, one concerning our MRC-funded work on the impact of chronic antipsychotic medication on rodent brain volume (as mapped using MRI) and on the challenges of linking MRI to post-mortem histology. Both talks sparked questions and plans for future work with colleagues in Oxford.
Year(s) Of Engagement Activity 2019
 
Description Invited seminar presentation, Wessex Immunology group, University of Southampton 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I gave an invited semainr to an immunology special interest group at the University of Southamptom on my MRC-funded work investigating the impact of antipsychotic drugs on the innate immune system. This sparked questions and debate and new opportunities for future collaborations
Year(s) Of Engagement Activity 2019
 
Description Invited seminar speaker, Centre for Addiction and Mental Health, University of Toronto, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I was invited to give a seminar at CAMH on the research I am currently undertaking, funded by this award. This has led to new collaborations with clinicans and ideas for new translational research projects.
Year(s) Of Engagement Activity 2017
 
Description Invited seminar speaker, Douglas Mental Health University Institute, McGill University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I was invited to give a seminar on my research funded by this award at the Douglas Mental Health University Institute, part of McGill University. This has led to the development of new collaborations and further vists and scientific exchange are planned for 2018.
Year(s) Of Engagement Activity 2017
 
Description Invited speaker, Heinrich Heine University Düsseldorf 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact I gave the guest lecture at the 2018 iBrain graduate school symposium at Heinrich Heine University Düsseldorf. This sparked questions from the students about our work and allowed me to interact with other faculty at HHU, including my existing collaborators there.
Year(s) Of Engagement Activity 2018
 
Description Invited speaker, University Medical Centre, Utrecht 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact The Brain Center Rudolf Magnus UMC Utrecht has initiated a monthly lecture series named after the founder of Biological Psychiatry in the Netherlands and emeritus Chair of Psychiatry in Utrecht, Herman van Praag.

The lectures will be for staff, researchers and residents within the Department of Psychiatry. These meetings tend to inform, educate and stimulate participants in their education and research.
Year(s) Of Engagement Activity 2018
 
Description Invited speaker: King's College London BRAIN centre open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact The department of Neuroimaging, King's College London organised an open day to celebrate the commissioning of the new BRAIN centre at KCL, which houses a state-of-the-art Bruker BioSpec 9.4T animal MRI scanner, which I utilise in the research conducted in my laboratory funded by this grant. As such, I was invited to present some of my work to the invtied attendees.
Year(s) Of Engagement Activity 2017
 
Description Symposium chair - Society for Biological Psychiatry meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact ~50 to 100 people attended an expert workshop on the metabolic side-effects of antipsychotic drugs used in the treatment of schizophrenia and related psychoses. This sparked questions from the audience and debate with the panel. Plans were made to repeat the event.
Year(s) Of Engagement Activity 2018
 
Description Symposium participant, German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I participated in an invited symposium at the 2018 DGPPN congress in which I presented our MRC-funded work on the impact of chronic antipsychotic drug exposure on the rat brain using MRI and post-mortem neuropathology. This sparked questions and debtate from the audience and follow up from Pharmaceutical companies who are developing novel antipsychotics.
Year(s) Of Engagement Activity 2018
 
Description Symposium participant, Schizophrenia International Research Society Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Conference symposium - Schizophrenia Internaitonal Research Society meeting 2018. >100 people attended to hear four scientific presentations on the role of the immune system in schizophrenia, which sparked questions and discussion afterwards and helped to establish new collaborations with other research groups
Year(s) Of Engagement Activity 2018
 
Description Symposium presentation at British Association for Psychopharmacology meeting (Brighton, UK) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I participated in a symposium entitled "Dysfunctional neuro-immune system interactions in psychiatric disorders and their relevance for novel treatment strategies" organised by Professor Joanna Neill (University of Manchester) and Dr Valeria Mondelli (King's College London). This aimed to review recent evidence from basic and clincial science for the role of inflammation in schizophrenia. The panel presented a well-balanced mix of preclinical and clinical aspects on this topic. The session was very well attended with a lively and well informed audience who posed several tough questions for the speakers. The symposium even received attention from Lancet Psychiatry who sent one of their representatives along, which has subsequently led to a paper now accepted for publication (but not yet online). Several ideas emerged following this session. These included putting on a special event to align the methodological approach of the many laboratories now working on maternal immune activation models in animals; preparing a review on the topic from a translational perspective, and going on tour with this session. This last idea has already been acted upon and BAP President Jo Neill submitted a follow on symposium with the same title, to the 26th IBNS-International Behavioural Neuroscience meeting to be held in Hiroshima, Japan from 26-30th June 2017. This has now been accepted and will be badged as a BAP symposium. Another BAP sponsored symposium on neuroinflammation will be held at the BNA-British Neuroscience Association Festival of Neuroscience in Birmingham from 10-13th April 2017. This symposium is titled "Microglia, neuroinflammation and psychiatric disease: biomarkers and therapeutic potential". Panels and chairs vary between these 3 symposia but I (Anthony Vernon) will be a speaker in both of these future symposia, maintaining continuity.
Year(s) Of Engagement Activity 2016
URL https://www.bap.org.uk/pdfs/BAPNewsletterDec2016.pdf
 
Description Symposium presentation at International Behavioural Neuroscience Society meeting (Budapest, Hungary) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact In partnership with my colleague Dr Davide Amato (Friedrich-Alexander University Erlangen-Nürnberg) I organised and participated in a symposium at the annual International Behavioural Neuroscience Society meeting held in Budapest, Hungary. Approximately ~100 people attended the session and there was a lively debate after the presentations. The goal of the symposium was to overview the most popular clinical concerns in schizophrenia in relation to antipsychotic drug treatment and to try to address these in light of new results from preclinical and clinical research, conducted by myself and the other speakers (3 European scientists including myself and Dr Amato). The symposium had a translational approach and appealed to both clinical and preclinical scientists committed to improve the health conditions of patients with schizophrenia.
Year(s) Of Engagement Activity 2016
 
Description Symposium speaker, Society for Biological Psychiatry Annual meeting 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Approximately 45 people attended our symposium at the 74th Annual meeting of the Society for Biological Psychiatry, entitled ""Assessing the Risks and Benefits of Antipsychotic Medication on Brain and Body: Data from a Double Blind Randomized Placebo-Controlled Clinical Trial, and Convergent Data from an Animal Model", which sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2019
 
Description Symposium speaker: Antipsychotic Treatment Update: Dissecting Molecular Mechanisms and Enhancing The Benefit-Risk Ratio. World Congress of Psychiatry, World Psychiatric Association, Berlin 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I participated as an invited speaker in a symposium entitled "Antipsychotic Treatment Update: Dissecting Molecular Mechanisms and Enhancing The Benefit-Risk Ratio" where I presented results from work funded by this award. The session was very well attended and sparked an excellent debate. Plans were made for a repeat event.
Year(s) Of Engagement Activity 2017
 
Description Symposium speaker: Microglia, neuroinflammation and psychiatric disease: biomarkers and therapeutic potential, British Neuroscience Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact More than 200 people attended this symposium at the British Neuroscience Association national meeting in Birmingham where I presented results from work funded by this award. The presentations sparked a lively debate amongst the audience and speakers.
Year(s) Of Engagement Activity 2017
 
Description Workshop organiser and speaker: Neuroadaptations to Antipsychotic drugs: Optimising Medication Use through a Deeper Understanding of Antipsychotic Drug Action in the Brain and Body. International Congress for Schizophrenia Research. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I organised and participated in the delviery of a workshop entitled "Neuroadaptations to Antipsychotic drugs: Optimising Medication Use through a Deeper Understanding of Antipsychotic Drug Action in the Brain and Body" at the 2017 International Congress for Schizophrenia Research. Approximately 50-60 people attend the event and there was an excellent discussion between the expert panel and the audience.
Year(s) Of Engagement Activity 2017