IVIG and Rituximab in Antibody-associated Psychosis

Research summary

Psychosis and schizophrenia are caused by factors associated with excess dopamine and abnormally low N-methyl D-aspartate receptor (NMDAR) functioning. There is increasing evidence for the role of inflammation in these disorders. We propose that one possible cause of psychosis and schizophrenia is the presence of antibodies in the blood that bind to the neuronal membrane in the brain. Since discovery of antibodies that bind to the NMDAR (NMDAR-ab) that cause encephalitis, we have discovered NMDAR-ab or voltage-gated potassium channel complex antibodies (VGKC-ab) in 6.5% of first episode psychosis (FEP) patients, without signs of encephalitis. This was replicated in an on-going MRC-funded study, where 8.8% of FEP patients possessed these autoantibodies.

Open-label experience suggests immunotherapy is effective in cases of full antibody-encephalitis. We recently reported on 18 patients with NMDAR-ab; 9 resolved on their own, or responded to antipsychotics, and 9 were resistant to up to 3 antipsychotics. Antipsychotic resistant patients were treated with corticosteroids alongside immunotherapy (plasma exchange (PLEX) or intravenous immunoglobulin (IVIG; a blood product containing antibodies), with subsequent mycophenolate or rituximab treatment), and responded well.

Informed by our feasibility study, this randomised double-blinded placebo-controlled trial aims to test the hypothesis that immunotherapy is an effective treatment for antibody-associated psychosis, either in FEP or relapse following remission, alongside antipsychotic medication if required. Trial immunotherapy consists of IVIG (2g/kg over 4 days) followed by two infusions of 1g rituximab(~day 30, then 14 days after the first infusion). This trial combines a rapid-action treatment (IVIG) to induce symptom remission, with a longer-action therapy (rituximab) to maintain remission. Before treatment, a number of assessments will be performed, including physician review and examination, laboratory investigations (including Ab-assays and safety blood tests and storing serum for future research), as well as clinical and cognitive assessments.

Main inclusion criteria

  1. Patient or legal representative is willing and able to provide informed consent.
  2. Acute psychosis for at least 2 weeks (defined as symptomatic on the PANSS scale by score equal to or greater than 4 on P1, G9, P3, P2, G5, N1, N4, N6).
  3. This may either be a first episode or relapse after remission (remission defined as PANSS3 on PANSS items P1, G9, P3, P2, G5, N1, N4, N6 for previous 6 months).
  4. Serum or CSF neuronal membrane autoantibodies at patholog

Main exclusion criteria

  1. Duration of current episode of psychosis greater than 24 months.
  2. Alternative coexisting severe neurological disease, including tumour, hippocampal sclerosis with refractory epilepsy, probable dementia with evidence of atrophy on brain imaging, moderate or severe learning disability.
  3. Any evidence of a current acute encephalopathy (for instance coma, seizures). • Hepatitis B, Hepatitis C or HIV positivity; severe hypogammaglobulinaemia.
  4. Previous malignancy (to be usually excluded unless agreed with CI).
  5. Pregnant, breast feeding or inadequate contraception if female.
  6. Hypersensitivity or absolute contra-indication to any study medication, murine proteins or excipients.
  7. Live vaccine within last 3 months.
  8. Previous treatment with rituximab in the past 12 months.
  9. Severe infection and severe heart failure.
  10. Any other medical illness or disability that, in the opinion of the investigator, would compromise effective study participation.
  11. Concurrent enrolment in other CTIMPs.

Funders and sponsors

Funders: Medical Research Council


Chief investigator

Prof Alasdair Coles

Contact details