MICA: STRATA - Schizophrenia: Treatment Resistance And Therapeutic Advances

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.

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.

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.