A randomised placebo-controlled trial of immunotherapy in patients with psychosis associated with anti-neuronal membrane antibodies (SINAPPS 2)

BACKGROUND
Psychosis is, according to the NHS website, "a mental health problem that causes people to perceive or interpret things differently from those around them. This might involve hallucinations or delusions." Psychosis and schizophrenia are common disorders which hinder people from flourishing, just as they are embarking on life as an adult. These disorders also cost the UK £12 billion per annum. Psychosis has many causes. Recently, we discovered that 5-10% of people with psychosis have antibodies in the blood that are capable of targeting receptors on the surface of brain cells. These receptors are either the "NMDA receptor" or "voltage gated potassium channel complex". The binding of antibodies to these receptors stops them from working properly, which in turn upsets normal brain function.

OUR IDEA
This proposal is based on the idea that the antibodies we find in the blood of people with psychosis are actually causing the problem. This means that we think these people have a basic problem with their immune system, and that the immune system is preventing their brain from working properly. So, in their particular case, psychosis is an "autoimmune disease".

OUR PROPOSAL
We will test this idea by getting eliminating these antibodies in their blood, and see whether this has a useful effect on psychosis symptoms.

THE PLAN
There are three stages to our proposal. (1) First of all, we need to find people with psychosis and antibodies in their blood. This involves testing the blood of around 2460 people with psychosis, over 3 years. To do this, we have set up several centres around England in which there are neurologists and psychiatrists interested in answering the question. We will employ research nurses to work from the centres, seeing as many people with psychosis as possible. Assisting them will be mental health nurses, working in the local trust, as well as an independent mental health advocate. This should identify around 160 people with antibody-associated psychosis, of which we estimate half will be interested in taking part in our trial. (2) Secondly, we will do a "randomised controlled trial" in which 80 people with psychosis and antibodies in their blood are randomly allocated to receive placebo or active immune treatment, alongside their antipsychotic drugs. For immune treatment, we propose people have "intravenous immunoglobulin" (IVIG) for four days, followed by two infusions of "rituximab".

THE TREATMENTS
- Intravenous Immunoglobulin is a blood product. Once the red cells have been removed from blood, the remaining "serum" is collected. Antibodies in the serum are extracted and then pooled together from many hundreds of individuals.
- Rituximab is a drug that causes long-lasting reduction in the "B cells" that are part of the immune system. It is used in many autoimmune diseases, like lupus and rheumatoid arthritis.
- All people in the trial can take normal antipsychotic drugs.

In three separate studies, we found 6-7% of patients with first-episode psychosis had autoantibodies to the N-methyl D-aspartate receptor or the voltage gated potassium channel complex, at high concentration: 3/46 patients in our initial study (Zandi et al., 2011), 14/230 in the MRC-funded PPiP1 study and 3/59 in PPiP2. We have also shown that 2/3 with high antibody levels are resistant to antipsychotics but respond well to immunotherapy (Zandi et al., 2014).
We propose a randomised double-blind placebo-controlled trial of immunotherapy as add-on to standard anti-psychotic treatment of antibody-associated psychosis, widening the inclusion criteria to improve recruitment to either first episode psychosis or in relapse.
Screening c. 2460 patients with psychosis to identify 160 suitable patients with associated autoantibodies, we shall recruit 80 patients into the trial, following each for 12 months. The primary outcome is time to remission of psychosis, sustained over 6 months (Andreasen et al., 2005). We estimate 20% of placebo-treated participants will achieve this endpoint at one year and that, having discussed with our patient partners, a meaningful treatment effect would be sustained remission in 50%. This can be detected at 80% power with a one-sided p=0.05 with n= 80, allowing for 24 drop outs.
A network of neurologists and psychiatrists at 6 sites (Oxford, Cambridge, Birmingham, Nottingham, Southampton and Manchester) are already testing the feasibility of recruitment and immunotherapy of this challenging patient group in the SINAPPS1 study funded by the Stanley Medical Research Institute (Sec 6.8). Now, SINAPPS2 will randomise patients to receive IVIG (2g/kg over 4 days) followed by two rituximab infusions over the next six weeks. Samples collected in this study from people with acute psychosis will be a substantial resource for later discovery science. This study has profound implications for the understanding and management of psychosis.

As well as patients with psychosis, and researchers into psychosis, the following people may benefit from this research: (1) manufacturers of intravenous immunoglobulin may see an increase in its use; (2) manufacturers of assays the neuronal membrane antibodies, such as the anti NMDA receptor antibody; (3) charities and government agencies seeking to improve funding for mental health research may benefit from the paradigm shift in treating psychosis that this work would bring; (4) the implications of a treatable form of psychosis, using immunotherapy, would be a challenge to international healthcare workers and their agencies; (5) the wider public would benefit by learning about the biological nature of psychosis, and hence, hopefully, removing some of the stigma around mental illness.

This work has the capacity to contribute to the nation's health by enhancing the quality of life of a subgroup of people with psychosis. This, in turn, will reduce the economic cost of caring for people with psychosis. It is realistic to imagine that, if this trial is positive, it will have fairly rapid implementation, as all of the required tools (antibody assay kits and therapies) are already available on the NHS. Staff working on this project will develop the skills required to integrate neurology and psychiatric services, which remains a significant obstacle in the delivery of effective healthcare across these disciplines.