Study of Immunotherapy in Autoantibody Positive Psychosis
Condition: Schizophrenia; Psychosis; Auto Immune Disorders
MeSH terms: Immune System Diseases; Autoimmune Diseases; Schizophrenia; Psychotic Disorders; Mental Disorders
Study type: Interventional

Summary: 
      Psychosis is a mental health problem that causes people to perceive or interpret things
      differently from those around them, often involving hallucinations or delusions. Psychosis
      and schizophrenia are common disorders which predominantly affect younger adults. Recently,
      the investigators discovered that 5-10% of people with psychosis have antibodies in the blood
      that are capable of targeting the surface of brain cells, specific to the
      N-methyl-D-aspartate (NMDA) receptor or voltage gated potassium channel complex, which the
      investigators believe may be causing the problem. Those positive for antibodies may have a
      problem with their immune system and this may prevent their brain from working normally. This
      trial aims to test the feasibility of removing or reducing the antibodies in patients' blood,
      using immunotherapy, and see if this improves symptoms of psychosis. Immunotherapy in this
      feasibility study will involve giving all patients steroid tablets and half of them will also
      receive a drug called "intravenous immunoglobulin" whereas the other half will have a
      procedure called "plasma exchange". The feasibility study is designed to identify which
      method of immunotherapy is most suitable for use in this patient population.

      Results from this will inform on the methodology used for a proposed larger randomised
      control trial.
    

Detailed description: 
      An autoimmune disease occurs when a person's immune system begins to respond to normal bodily
      substances and tissues as if it were foreign or related to disease. There are a number of
      autoimmune disorders, some of which can affect the brain by targeting the surface of brain
      cells, for example signalling proteins like the NMDA receptor or voltage gated potassium
      channel complex. Some cases of encephalitis, a disorder of brain inflammation that can be
      autoimmune, are caused by these antibodies, but often present with psychotic experiences,
      such as hallucinations, and may see a psychiatrist at this stage, before they go on to
      experience seizures and brain swelling, and are seen by a neurologist. These patients are
      treated with immunotherapy, and after treatment see a reduction in both seizures and
      psychotic symptoms.

      Recently the investigators identified patients with psychosis who test positive for these
      antibodies, but do not go on to experience these other symptoms of encephalitis. It has been
      suggested that these patients suffer from an autoimmune disorder similar to the encephalitis
      described above. Small pilot studies in these antibody positive psychosis patients have shown
      various immunotherapies can reduce both symptoms of psychosis and number of autoantibodies
      present in their blood. A randomised clinical trial (RCT) is required to confirm this.
      However a feasibility study is required first to investigate whether it is possible to
      deliver the immunotherapy treatments in patients with psychosis. The treatments require an
      infusion over a few hours (IVIG) or an admission to an acute medical ward for several
      days(plasma exchange). Both may be challenging for people who are paranoid or agitated. The
      investigators need to assess whether it is possible to deliver these treatments before
      proceeding to a large scale, clinical trial.

      This is a multicentre, randomised, uncontrolled, open label feasibility study. Patients with
      psychosis and a positive blood test for antibodies will be identified from one of 24
      recruiting centres across England. They will undergo screening assessment for eligibility
      (interview with psychiatrist and neurologist and baseline investigations where possible,
      including MRI, EEG and lumbar puncture) and give informed consent for the study. A further
      blood sample (10ml) will be taken for future research. 10 Participants will be randomised to
      one of two clinical care pathways: either an infusion of intravenous immunoglobulins, or
      plasma exchange treatment. Both groups will receive steroid tablets, and both groups will
      continue to receive psychiatric treatment, including antipsychotic medication, as normal.

      At two months after randomisation the research team will speak to the treating clinicians to
      gather the primary outcome measure which is whether the patient received the allocated
      treatment within two weeks of allocation. The researchers may also confirm this outcome from
      the clinical records.
    

Intervention name(s): Plasma Exchange; Intravenous immunoglobulin
Intervention type(s): Biological; Biological
Intervention description(s): PLEX is a procedure in which the subject's blood is passed through a medical device which separates out plasma from the other blood components, and replaces the plasma with albumin or plasma or other colloid. PLEX therefore removes circulating pathogenic antibodies, and furthermore therapeutic benefit after PLEX supports an antibody mediated pathogenesis of disease. In PLEX, 200-250 mL plasma per kg body weight is exchanged typically over 7-14 days using 5% albumin as replacement, often at alternate days which increases the amount of immunoglobulin removed due to equilibrium effects. PLEX modality (centrifugation or filtration), type of anticoagulation, and dose scheduling will be determined by local centre practice.; Active Comparator: Intravenous Immunoglobulin (IVIG) IVIG is a pooled blood product from 3000-100,000 human blood donors with direct immunomodulatory effects.
IVIG will be given at a dose of 2g/kg over 4 days. Dosing at 2g/kg is established in neurological disorders, with limited evidence that lower doses are less effective although adequate dosing studies have not been performed.
Other intervention name(s): PLEX; IVIG
Intervention MeSH terms: Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Schizophrenia; Psychosis; Mental Health; Autoimmunity; Psychoneuroimmunology