MICA: STRATA - Schizophrenia: Treatment Resistance And Therapeutic Advances

Lead Research Organisation: King's College London
Department Name: Inst of Psychiatry School Offices

Abstract

People with schizophrenia suffer from a range of symptoms including hallucinations (such as hearing voices), delusions (false beliefs) and thought disorder (thoughts not flowing in a logical way), as well as 'negative symptoms' such as a lack of motivation and withdrawal from social contact. Currently, antipsychotic medication is the mainstay of treatment of schizophrenia and all existing antipsychotic medications are thought to work by acting to reduce transmission of a brain chemical called dopamine. However, even after attempts to treat the disorder with two different antipsychotics, around 30% of patients still fail to improve. When this happens, the medical guidelines recommend treatment with a different drug called clozapine. However clozapine has several side effects and requires regular blood tests, so people do not like taking it. It is also ineffective in some patients.

The result is that a large number of patients spend too long on ineffective drugs which impact greatly on their mental health, well-being and quality of life whilst the costs of ineffective treatment is a huge financial burden to the NHS, consuming 25-50% of the total national mental health budget.

This set of studies aims to build on new evidence from neuroimaging and genetics studies suggesting that those who do not respond may actually have a completely different neurochemical abnormality causing their symptoms, involving a different chemical called glutamate. There are some new medicines under development that we hope will help people whose illness has not responded to standard medicines acting on dopamine.

We aim to develop a method to predict, ultimately as early as first admission, which patients will respond to standard dopamine drugs, and which people are instead more likely to respond to the new glutamate drugs. This will allow people to receive the medicines they need straight away, without having to try ineffective drugs first.

The proposed research programme is broken down into several parts. The first set of studies will use cutting edge brain scans to confirm that those patients who don't respond to standard treatments have higher glutamate levels, but normal dopamine levels. We will then develop tests, using genetic markers and other information, to identify in advance which people will respond to which medication types. If this is successful, we will then conduct a clinical trial to see whether prescribing medicines according to the test results gives better outcomes for patients than the 'trial and error' method by which we prescribe medicines at present. Lastly we will investigate economic benefits and, with Service User groups, investigate the acceptability of an early identification tool from the patient perspective.

Technical Summary

A third of patients with schizophrenia fail to respond to standard dopamine-blocking antipsychotic drugs. This is a major clinical problem, causing immense personal and family suffiering and costing billions in health, social care and lost productivity. Two converging streams of findings from our consortium suggest that abnormalities of the glutamate system may identify patients who are non-responsive to dopamine blockers (T-Non-Resp). Imaging studies have shown that T-Non-Resp patients have abnormal glutamate systems, but seemingly normal dopamine systems. Meanwhile, genetic research has demonstrated that T-Non-Resp patients have an excess of genetic abnormalities in glutamate system pathways, but fewer abnormalities in dopamine pathways, than typical patients with schizophrenia. Fortunately, several pharmaceutical companies in our consortium are already developing drugs acting on the glutamate system which are currently in phase II/III.

OBJECTIVES: (1) To develop an imaging and/or genetic based stratification strategy that will help identify patients who do not respond well to current dopamine-blocking treatments; (2) To develop a multi-centre clinical trials network to deliver standardised stratified clinical trials; (3) To develop a quantitative understanding of the health economic implications, patient and clinician acceptability of such an approach; (4) Using this network, to conduct a proof-of-concept stratified medicine trial, to test the ability of the stratifier to predict response to an add-on glutamatergic drug and improvements that a stratified approach would make to both clinical and pharmacoeconomic outcomes.

Planned Impact

The broad aims of the current project are to develop a means to identify predictors of treatment-resistance in patients with schizophrenia, who may hence require a different type of medication; and then to work with Pharma collaborators to examine efficacy of novel medications which act on that neurochemical system. This research program has significant and far-reaching implications to a wide variety of interest groups, and could have potentially profound effects on patients' well-being, illness course and patient outcome, financial burden to the NHS, investment and development focus of Industry, NICE guidelines, as well as our understanding of schizophrenia.

Impact on Patients
At present, patients with schizophrenia may spend many years taking ineffective medication. During this time, patients experience persistent clinical symptoms, which coupled with medication side-effects, profoundly affect their quality of life, subjective well-being, and broader functional and social status. This time should be shortened as a result of this work.

Clozapine, which is currently the only medication currentllicenced for "treatment resistant" schizophrenia, is also associated with serious side-effects, such as agranulocytosis. Less clozapine will be used as more patients will receive novel 'glutamate' drugs which do not produce these side effects. Improvements in clinical efficacy may improve adherence. The new glutamate drugs are already being developed thus positive findings could contribute to acceleration of the clinical availability of these medicines to patients.

Clinical trials
Clinical trials typically exclude patients with "treatment resistant" schizophrenia, as pharmaceutical companies see them as unlikely to respond to new drugs and therefore a "bad bet" for trialling their new medicines. Patients with treatment non-response are therefore severely disadvantaged, as there is little research carried out in this group, and thus little evidence on which to base treatment decisions in this group. However our findings suggest that such patients are precisely those most likely to benefit from glutamatergic agents. We hope that this will lead to the inclusion of such patients in drug trials in the future.

NHS
About 30% of schizophrenia patients treated with antipsychotics are resistant to first-line 'dopaminergic' medication. Long-term ineffective treatment is both time-consuming and enormously costly to the NHS. Treatment non-responsive patients consume 25-50% of the total national mental health budget. Early identification and appropriate treatment of patients with the correct medicines (patients would otherwise have been deemed "treatment Resistant") would profoundly reduce financial burden to the NHS.

NICE guidelines
Identification of a subgroup of patients who respond to glutamatergic and not dopaminergic compounds would necessary lead to a revision of NICE guidelines of treatment of patients with schizophrenia. Stratification of patients with glutamatergic abnormalities, and medicines that act on this system, would likely result in NICE recommending that new patents are screened (according to the stratification tool classifier we will develop) and hence prescribed either a dopaminergic or glutamatergic compound accordingly.

Drug Development by Pharmaceutical Industry
There has been little advance in the development of novel antipsychotics over the past decade. The potential for novel antipsychotics which act on a different neurotransmitter has several implications. Positive findings would open a new avenue of drug development using stratification to identify patients who will respond to novel drugs. Consequent investment in this direction of pharmaceutical development would lead to novel discoveries and greater understanding of glutamate in schizophrenia. There is also clear financial incentive to develop novel drugs which target populations previously seen to be non-responsive to treatment.

Publications

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Beck K (2015) Prevalence of serum N-methyl-D-aspartate receptor autoantibodies in refractory psychosis. in The British journal of psychiatry : the journal of mental science

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Fleischhacker WW (2014) Polypharmacy: the good, the bad and the ugly. in The international journal of neuropsychopharmacology

 
Description Consultant to POMH
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact The UK prescribing observatory on Mental Health asked for our expertise in developing and reviewing their national audit of clozapine prescribing oin the UK
 
Description Contribution to National guidelines on antipsychotic prescribing from the British Association of Psychopharmacology
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Membership of Nordic Research Board
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
Impact These impacts arise through the research programmes funded by the Nordic Research Council.
 
Description Clinical training Fellowship
Amount £243,384 (GBP)
Funding ID MR/P001378/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Commercial grant
Amount £208,425 (GBP)
Funding ID 418952 
Organisation H. Lundbeck A/S 
Sector Private
Country Denmark
Start 12/2017 
End 06/2019
 
Description Commercial study (RCT)
Amount £85,436 (GBP)
Organisation H. Lundbeck A/S 
Sector Private
Country Denmark
Start 04/2018 
End 11/2019
 
Description KCL Application for a Mental Health Data Pathfinder award
Amount £1,497,000 (GBP)
Funding ID MC_PC_17214 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2018 
End 03/2020
 
Description MRC Mental Health Data Pathfinder
Amount £1,497,000 (GBP)
Funding ID MC_PC_17214 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2018 
End 03/2020
 
Description MRC Project Grant
Amount £68,000 (GBP)
Funding ID MR/L003988/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 08/2018
 
Title STRATA database 
Description The STRATA database comprises all the data collected as part of the STRATA collaboration 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact The study is ongoing but the data will be made available at the close of the study. 
 
Description ANEW clinical trial 
Organisation H. Lundbeck A/S
Country Denmark 
Sector Private 
PI Contribution National coordinating investigator for the UK (3 sites). Access to patient populations.
Collaborator Contribution Financial
Impact Outputs will be generated in 2019
Start Year 2018
 
Description Cardiff University 
Organisation Cardiff University
Department Division of Psychological Medicine and Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution As the lead partner in the collaboration we provide leadership, management, clinical and research expertise, and access to patient cohorts.
Collaborator Contribution Expertise in genetics, infrastructure for genetic sample processing and analyses, clinical and research expertise, and access to patient cohorts.
Impact See main STRATA outputs
Start Year 2014
 
Description Collaboration with Lundbeck 
Organisation H. Lundbeck A/S
Country Denmark 
Sector Private 
PI Contribution Expertise in treatment resistant schizophrenia, access to data, access to patient cohorts, research infrastructure, background IP
Collaborator Contribution Expertise in data analysis, expertise in psychopharmacology, opportunity to work with industry and to translate our research.
Impact Research has just started, uotputs will be available by end 2018
Start Year 2016
 
Description Collaboration with University of Aarhus 
Organisation Aarhus University
Country Denmark 
Sector Academic/University 
PI Contribution Leadership, clinical and research expertise, and access to patient cohorts.
Collaborator Contribution Research expertise, and access to patient cohorts.
Impact See main STRATA outputs
Start Year 2014
 
Description Edinburgh University 
Organisation University of Edinburgh
Department Division of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution As the lead partner in the collaboration we provide leadership, management, clinical and research expertise, and access to patient cohorts.
Collaborator Contribution Clinical and research expertise, and access to patient cohorts.
Impact see main list of STRATA outputs
Start Year 2014
 
Description Queens University Belfast 
Organisation Queen's University Belfast
Department Centre for Public Health (CPH)
Country United Kingdom 
Sector Academic/University 
PI Contribution As the lead partner in the collaboration we provide leadership, management, clinical and research expertise, and access to patient cohorts.
Collaborator Contribution Clinical and research expertise, and access to patient cohorts.
Impact See main STRATA outputs
Start Year 2014
 
Description University of Manchester 
Organisation University of Manchester
Department Community-Based Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution As the lead partner in the collaboration, we provide leadership, management, clinical and research expertise and patient populations.
Collaborator Contribution Clinical and Research expertise and patient populations.
Impact see STRATA outputs
Start Year 2014
 
Description University of Nottingham 
Organisation University of Nottingham
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution As the lead partner in the collaboration we provide leadership, management, clinical and research expertise, and access to patient cohorts.
Collaborator Contribution Access to patient cohorts.
Impact See main STRATA outputs
Start Year 2014
 
Description Article in YourVoice 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact An article describing our research was published in Your Voice, the magazine of the mental health charity, Rethink Mental Illness. The research was the main item featured on the front cover.
Year(s) Of Engagement Activity 2016
 
Description STRATA cited in House of Lords discussion 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact A member of the House of Lords identified our study as indicative of the type of research that should be prioritised in the UK. He made reference to the study in a speech to the House of Lords.
Year(s) Of Engagement Activity 2015