Identifying the prevalence of antibodies to neuronal membrane targets in first episode psychosis

In the last ten years there have been breakthroughs in the discovery of new treatment responsive causes of limbic encephalitis. This is a rare, life threatening brain disorder. These new causes have been antibodies against targets on the surface of brain cells. In the descriptions of these new disorders patients often present with promninent psychiatric symptoms, with symptoms of psychosis such as hallucinations and delusions and disordered thinking and impaired memory. However they also develop difficulties with fits, loss of unconsciousness, blood pressure control or electrolyte disturbance which means that they end up under the management of neurologists or intensive care specialists rather than psychiatrists. We were interested whether a proportion of patients with purely psychiatric symptoms of the disorder would also have these antibodies. We therefore tested 47 patients with a first episode of psychosis, without other features of limbic encephalitis and found that 3 of them did have these antibodies. We have since identified, without systematic screening a further 9 patients, and have treated 4 of these by treating their immune system rather than traditional psychiatric medication. This gives further support to the theory that the antibodies are causing the psychosis in these patients. We now wish to establish just how common this disorder is. We want to screen a larger number of patients for all known antibodies that can cause limbic encephalitis. This will help us to estimate how significant a disorder this is, and help with planning clinical services.

anti-NMDAR and anti-VGKC complex antibodies have been identified as treatment responsive causes of limbic encephalitis. In both disorders psychotic symptoms are the predominant presenting symptoms. There are strong theoretical reasons to associate both of these antibodies with psychotic illness. We have identifed cases of primary psychotic illness, without the other features typical of disorders, with both of these antibodies. We have identified some cases prospectively and have successfully treated 4 cases solely with immunotherapy. These preliminary findings suggest that these antibodies are pathogenic in some cases of first episode psychosis. We therefore wish to establish the prevalence of these antibodies in a cohort of patients at first presentation psychosis. This is a pilot study to establish the prevalence of the disorder. If the number of cases warrants further investigation we would then wish to undertake a larger project to fully characterise the phenotype of this disorder and guide treatment planning in first episode psychosis

Health:
In other cases of limbic encephalitis caused by these antibodies patients respond to immunotherapy, especially if treatment is started early and aggressively (Irani et al 2010). A significant proportion of cases are paraneoplastic, most commonly associated with ovarian/testicular teratoma. In these cases early removal of the teratoma is also associated with an excellent outcome. In the cases of primary psychosis with antibodies that we have treated with immunotherapy in each case the patient was an inpatient on a psychiatric ward when identified, responded to steroids and/or plasma exchange and was able to be discharged from hospital afterwards. There is therefore the potential for significant benefit for the individual patients, with an identifiable, treatable cause for their psychotic illness.

Wealth:
Psychotic illnesses accounts for a huge cost to the economy, both through direct and indirect costs. Psychosis accounts for more than 50% of all psychiatric inpatient beds. The peak age of onset is in adolescence and at the moment is considered a lifelong disorder. Current treatments are helpful for some symptoms of the disorder, but do not change the illness course. If an aetiology can be identified in even a small proportion of patients there will be significant gains to the economy.

Psychiatric services
The researchers in the application work in academic health science centres with considerable infrastructure to support the rapid translation of new evidence into practice (NIHR BRCs and CLAHRC). The service implications of this research may be the reconfiguration of mental health services to allow access to appropriate investigations and treatments for this new disorder.

Commercial
If novel antigens of relevance to psychosis are discovered, Euroimmun AG would be in a position to develop multiple antigen testing kits specifically for psychiatric disorders, in collaboration with the applicants.