MICA: Immuno-psychiatry: a consortium to test the opportunity for immunotherapeutics in psychiatry

Lead Research Organisation: University of Cambridge
Department Name: Psychiatry

Abstract

Depression is a very common and potentially severe disorder. There are some treatments already available for depression, like the SSRI ("Prozac") class of anti-depressants. However, not all patients respond well to SSRI treatment: about a third of patients remain depressed. This is an area of medicine where there is a strong need to do a better job therapeutically. But there has been relatively slow progress in delivering new medicines in the last 15 years.

We propose to explore and test a radically innovative approach to finding new drug treatments for depression (and potentially other psychiatric disorders). In this project, we will focus on the idea of using anti-inflammatory drugs (like aspirin) to treat depression, especially in patients who have not responded well to SSRI treatment.

Recent scientific research has highlighted that inflammation is a major risk factor for depression. Some degree of depression is very common among patients with medical inflammatory disorders, like rheumatoid arthritis. Patients who are primarily depressed, and do not have a medical inflammatory disorder, generally have somewhat higher blood levels of inflammatory markers than non-depressed people. There is already some evidence that inflammation can block the therapeutic effects of SSRI anti-depressant drugs. And there have been some reports that anti-inflammatory drugs can have anti-depressant effects, at least in some patients with depression.

On this basis, we will address 4 key questions that need to be answered more clearly and completely before we can consider potentially more serious investment in clinical development of new anti-inflammatory drugs for depressive symptoms linked to abnormal states of the immune system.

1) Is inflammation linked to SSRI treatment resistance? 2) Do anti-inflammatory drugs have anti-depressant effects? These questions will be addressed mainly by analysis of several, large, prior datasets. For example, we will use anonymised NHS data as well as clinical trial data released by the industrial partners (GlaxoSmithKline and Johnson & Johnson) to look for new evidence linking inflammation to depressive symptoms that respond poorly to SSRI treatment. To test a particular mechanistic reason why inflammation might cause SSRI treatment failure, we will also do a number of small lab experiments, using blood samples from healthy volunteers (University of Edinburgh and GSK).

3) Can we validate immune biomarkers for depression and treatment resistance? 4) Can we use biomarkers of depression to predict which anti-inflammatory drugs are most likely to be anti-depressant? Essentially what we mean by these questions is can we develop a blood test that we can use to predict which patients with depressive symptoms are most likely to benefit from which anti-inflammatory drug? To address these questions we will again priortise analysis or re-analysis of existing data including several large biomarker collections (released by GSK) and major studies conducted by the academic partners (University College London, King's College London). We will also conduct some additional lab experiments on human blood samples.

We aim to complete this project within 2 years and then review the case for further investment in direct clinical trials of new anti-inflammatory drugs for treatment of depression in patients who have a blood test result indicating that they are inflamed and unlikely to respond well to existing anti-depressant drugs.

Technical Summary

The project will build on recent evidence that activation of the innate immune system is often associated with depressive states, and that some anti-inflammatory drugs may have anti-depressant effects, at least in some patients. It is also known that inflammatory states can modify peripheral and central monoamine signalling, and this might explain preliminary clinical data indicating that peripheral inflammation predicts resistance to monoaminergic anti-depressants.

To explore and test the therapeutic implications of these observations, we will analyse or re-analyse large prior clinical, epidemiological or experimental datatsets. NHS data will be accessed by an ethically approved system for anonymizing electronic health records in two NHS mental health trusts linked to academic partners (KCL and Cambridge). Longitudinal datasets on general population samples, including biomarker measurements, will be available through partnership with the Whitehall II and ELSA epidemiological studies (UCL). Data on randomized placebo-controlled clinical trials of anti-inflammatory drugs for medical disorders will be re-analysed with a focus on mental health questionnaire scores completed as safety endpoints (GSK and J&J). Genetic and biomarker (PBMC microarray, proteomic) case-control collections on patients with depression and other psychiatric and medical disorders will also be released by GSK. Pharmacogenetic effects will be tested by analysis of genetic and microarray data in partnership with the GENDEP study (KCL).

We will also conduct a small number of new lab experiments to measure gene expression changes in human macrophages and other PBMCs in response to pro-inflammatory and pharmacological challenges ex vivo (Edinburgh, GSK).

There will be a strong underpinning technical focus on bioinformatics and advanced statistical methods for systems or network-level analysis and visualization of complex immunophenotypes and their relationships to genetic variation (BSU).

Planned Impact

The consortium is designed to have impact on decision making about new drug development in psychiatry. The recent track record of commercial R&D investment in new drugs for depression or psychosis is poor and overall industry spend on neuroscience R&D is reducing as decision-makers prefer less risky investments.

In this context, immuno-psychiatry is potentially attractive for a number of reasons. Almost all pharmaceutical and biotech companies have expertise and assets in immunology, inflammation or biopharmaceuticals. So demonstrating that mental health disorders are immunologically tractable moves an otherwise marginal therapeutic area closer to the industry's scientific centre of gravity. More specifically, immuno-psychiatry also addresses one of the principal special risks of drug development in psychiatry - the lack of quantitative, mechanistic biomarkers of disorder or therapeutic effect. By refocusing on the immune system (not the nervous system) as the target tissue for treatment of mental health symptoms, there is an opportunity to develop peripheral blood biomarkers of immune states; blood tests that could be used, for example, to stratify depressed patients most likely to respond to an anti-inflammatory drug, and/or least likely to respond to a monoaminergic anti-depressant. If such peripherally accessible and mechanistically specific biomarkers could be validated (initially for depression) that would represent a major step toward derisking the path of clinical drug development in psychiatry.

The consortium includes two major pharmaceutical companies (Johnson & Johnson and GlaxoSmithKline) as partners. If the results of the research, which has been planned explicitly to test the promise of immuno-psychiatry, are considered positive this is likely to have immediate impact on the planning and conduct of clinical studies of new drugs for psychiatric indications. Most optimistically, the research could have commercial and social impact by catalysing industrial re-investment in areas of major unmet clinical need, associated with massive personal, social and economic costs.

Publications


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Barnes J (2017) Genetic Contributions of Inflammation to Depression. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Egeland M (2015) Molecular mechanisms in the regulation of adult neurogenesis during stress. in Nature reviews. Neuroscience
Hepgul N (2016) Transcriptomics in Interferon-a-Treated Patients Identifies Inflammation-, Neuroplasticity- and Oxidative Stress-Related Signatures as Predictors and Correlates of Depression. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Hodgson K (2016) Transcriptomics and the mechanisms of antidepressant efficacy. in European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
 
Description Citation in MRC Mental Health Research Strategy
Geographic Reach National 
Policy Influence Type Citation in other policy documents
URL https://www.mrc.ac.uk
 
Description Wellcome Trust Strategy Award: Neuroimmunology of mood disorders and Alzheimer's disease
Amount £5,000,000 (GBP)
Funding ID 104025 
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2015 
End 12/2020
 
Description Janssen, GSK and MRC ImmunoPsychiatry 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution The academic partners (Cambridge, MRC BSU, KCL, UCL, Southampton, Edinburgh) have provided expertise in affective disorders, bioinformatics, macrophage biology, health informatics and epidemiology; as well as access to existing microarray and epidemiological datasets. The academic partners have also substantively contributed to analysis of microarray datasets from case-control studies of depression previously collected by the industry partners.
Collaborator Contribution Janssen has contributed expertise in clinical trial data analysis, bioinformatics and neurobiology of mood disorders. Specifically, Janssen has commissioned in-house re-analysis of 12 phase II/III clinical trials of anti-inflammatory drugs for non-psychiatric disorders (eg rheurmatoid arthritis) that have included mental health questionnaires as safety endpoints. These data have been re-analysed to test the hypothesis that anti-inflammatory drugs have anti-depressant effects in patients with comorbid depressive symptoms in the context of medical disorders. Janssen has also commissioned in-house re-analysis of microarray data collected as part of a prior case-control study of depression (N~100 per group). GlaxoSmithKline has contributed project management skills to support the overall organization of the consortium including regular scheduling of teleconferences and face-to-face meetings, legal negotiation of the consortium agreement between parties, and routine monitoring of work package delivery against timeline and budgetary milestones. GlaxoSmithKline has also contributed expertise in clinical trial data analysis and has commissioned in-house re-analysis of 8 phase phase II/III clinical trials of anti-inflammatory drugs for non-psychiatric disorders (eg rheurmatoid arthritis) that have included mental health questionnaires as safety endpoints. These data have been re-analysed to test the hypothesis that anti-inflammatory drugs have anti-depressant effects in patients with comorbid depressive symptoms in the context of medical disorders. The analysis of these data has been closely coordinated with the parallel effort by Janssen with the intention of producing a single joint publication. GlaxoSmithKline has also contributed expertise in bioinformatics and has enabled access to a microarray dataset collected as part of a prior case-control study of depression (N~100 per group). Analysis of these data has been led by Cambridge and MRC Biostatistics Unit and closely coordinated with the parallel effort by Janssen with the intention of producing a single joint publication.
Impact There are no outputs yet published from the GSK and Janssen engagement with the consortium but at least two major papers are in preparation - one reporting the combined analysis of two independent case-control microarray studies of depression and one reporting the combined analysis of mental health outcome data from about 20 phase II/III clinical trials of anti-inflammatory drugs in non-psychiatric indications.
Start Year 2014
 
Description Janssen, GSK and MRC ImmunoPsychiatry 
Organisation Janssen Research & Development
Country Global 
Sector Private 
PI Contribution The academic partners (Cambridge, MRC BSU, KCL, UCL, Southampton, Edinburgh) have provided expertise in affective disorders, bioinformatics, macrophage biology, health informatics and epidemiology; as well as access to existing microarray and epidemiological datasets. The academic partners have also substantively contributed to analysis of microarray datasets from case-control studies of depression previously collected by the industry partners.
Collaborator Contribution Janssen has contributed expertise in clinical trial data analysis, bioinformatics and neurobiology of mood disorders. Specifically, Janssen has commissioned in-house re-analysis of 12 phase II/III clinical trials of anti-inflammatory drugs for non-psychiatric disorders (eg rheurmatoid arthritis) that have included mental health questionnaires as safety endpoints. These data have been re-analysed to test the hypothesis that anti-inflammatory drugs have anti-depressant effects in patients with comorbid depressive symptoms in the context of medical disorders. Janssen has also commissioned in-house re-analysis of microarray data collected as part of a prior case-control study of depression (N~100 per group). GlaxoSmithKline has contributed project management skills to support the overall organization of the consortium including regular scheduling of teleconferences and face-to-face meetings, legal negotiation of the consortium agreement between parties, and routine monitoring of work package delivery against timeline and budgetary milestones. GlaxoSmithKline has also contributed expertise in clinical trial data analysis and has commissioned in-house re-analysis of 8 phase phase II/III clinical trials of anti-inflammatory drugs for non-psychiatric disorders (eg rheurmatoid arthritis) that have included mental health questionnaires as safety endpoints. These data have been re-analysed to test the hypothesis that anti-inflammatory drugs have anti-depressant effects in patients with comorbid depressive symptoms in the context of medical disorders. The analysis of these data has been closely coordinated with the parallel effort by Janssen with the intention of producing a single joint publication. GlaxoSmithKline has also contributed expertise in bioinformatics and has enabled access to a microarray dataset collected as part of a prior case-control study of depression (N~100 per group). Analysis of these data has been led by Cambridge and MRC Biostatistics Unit and closely coordinated with the parallel effort by Janssen with the intention of producing a single joint publication.
Impact There are no outputs yet published from the GSK and Janssen engagement with the consortium but at least two major papers are in preparation - one reporting the combined analysis of two independent case-control microarray studies of depression and one reporting the combined analysis of mental health outcome data from about 20 phase II/III clinical trials of anti-inflammatory drugs in non-psychiatric indications.
Start Year 2014
 
Title Sirukumab Phase 2 trial for Major Depressive Disorder 
Description Sirukumab is an anti-IL6 antibody in development for inflammatory disorders by GSK and Janssen. In 2015, Janssen initiated a phase 2 trial of sirukumab for patients with MDD suboptimally responsive to conventional anti-depressants and with baseline C-reactive protein greater than 3mg/L. MRC ImmunoPsychiatry consortium members contributed to the protocol for this study, including provision of supporting data from re-analysis of mental health endpoints from clinical trials on sirukumab and other anti-inflammatory drugs in non-psychiatric indications. The study is currently recruiting and is expected to read out in 2017. To the best of our knowledge, this is the first immunologically stratified phase 2 study of an anti-inflammatory drug for depression (or any other psychiatric disorder). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact The study is currently recruiting and will read out in 2017 
URL https://clinicaltrials.gov/ct2/show/NCT02473289?term=sirukumab+depression&rank=1
 
Description Annual Psychoneuroimmunology Research Society (PNIRS) Conference 
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 PNIRS is the leading research society internationally dedicated to understanding bidirectional interactions between immune and nervous systems, and past and current members of PNIRS have been responsible for generating much of the empirical data and conceptual framework now being built on by immunopsychiatry. The conference is organised by Dr Neil Harrison (MRC Consortium collaborator) and will feature presentations of the consortium's work.
Year(s) Of Engagement Activity 2016
URL http://pnirs.org/meetings/index.cfm
 
Description RCPsych ImmunoPsych Symposia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Royal College of Psychiatrists Annual Meeting - symposia presentations to practitioners on status of inflammation as a cause / predictor of treatment resistant depression (Prof C Pariante)
Year(s) Of Engagement Activity 2015