Improve diagnosis of psychotic disorder of autoimmune origin

Psychotic disorders, such as schizophrenia and bipolar disorder, are severe
mental disorders that usually have profound implications for the health and
daily lives of patients and their families. Approximately 1% of the population
has a severe psychotic disorder and this often starts between the age of 15 and
35 years. The possibilities for treatment are still very limited and focused on
the control of symptoms with antipsychotics but fail to effectively suppress
the disease process. A lack of treatment rationale follows from the fact that
we still do not understand how psychotic disorders arise. We also suspect that
these disorders are actually a manifestation of different disease processes.
However, we now believe that we are on track to find out on one of these
disease processes and think that this can have very beneficial effects on the
treatment of the patients. It has recently been shown that antibodies against
brain proteins may cause an autoimmune disease and that patients with this
disease can have severe psychiatric and neurological symptoms. We and others
have seen that occasionally neurological symptoms may be absent. We suspect
that a portion of the patients with a psychotic disorder actually has an
autoimmune disease and that this subgroup should be treatable as is the case
with other auto-immune diseases.

The main objective of this project is to study the prevalence of autoantibodies
against the NMDA-r, AMPA-r, GABAB-r and VGKC-complex (LGI-1 and Caspr-2) in
patients with an early onset psychotic disorder. Patients suffering from stable
but also acute psychoses will be included in the study because it is thought
that during such periods the level of autoantibodies is increased, perhaps in
some cases above the level of detection.
For this, blood (and CSF samples in stable patients) will be collected and
analyzed. Differences in the spectrum of neuropsychiatric symptoms between
patients with different autoantibodies will be correlated.
Furthermore, the pathogenic mechanisms of how these neuronal autoantibodies
affect neuronal function will be studied by testing the effect of cloned
monoclonal antibodies on neurotransmitter receptors/ion channels in vitro.
The BBB dysfunction will be characterized to describe the state and the role of
this barrier in this pathology.

This study concerns a cross-sectional, observational and descriptive study
investigating autoantibody prevalence as correlated with cognitive,
psychopathological and neurologic profiles in psychosis (see point 8.1.2).
Early onset psychotic patients will participate in the study. They will donate
blood and CSF and will undergo neuropsychological tests. The study consists of
one or two visits, which will take place at the azM as a single center study
(see section 8.3) during 4 years. Patients will receive individual codes that
will be used to store the clinical data of the neuropsychological and
neurological tests. The individual codes will also be used as a label for the
serum and CSF obtained from these patients for antibody testing. The
correlation studies (antibodies v psychiatric & neurologic profiles) will be
performed blinded by a researcher.

We seek to identify differences in the spectrum of neuropsychiatric symptoms
between patients without and with autoantibodies targeting NMDA-r, AMPA-r,
GABAB-r, LGI1 and Caspr-2 (see section 8, Methods).

We will isolate B-cells in the blood of selected patients (with autoantibodies,
see above) and we will clone the autoantibody genes and produce relative large
quantities of monoclonal antibodies (see section 8, Methods). These
autoantibodies will be used in in vitro experiments in which receptors are
expressed in cell cultures to study the effector functions of the
autoantibodies and correlate them with the clinical characteristics.

The BBB integrity of the patients will be also studied quantifying the levels
of well-known proteins like albumin and immunoglobulins in blood and in CSF
(See section 8.1.2 Secondary study parameters/endpoints.

No serious side effects are foreseen. The neuropsychological tests and
questionnaires are non-invasive. Blood collection and a single CSF sample
extraction are mild and low risk procedures. The collection of blood has a
small risk of hematoma and the lumbar puncture involves only a minor risk to
the patient. With the current use of atraumatic needles, the occurrence of a
drop in pressure (which may cause a serious headache) is a rare event. In
addition, the possibility of a drop in blood pressure following the lumbar
puncture is very small. After the dorsal puncture the patient may go home
unaccompanied (also if self-driving by private car) after having taken a rest
period of 15 min. The whole study can be completed in one or two visits,
consuming 4-5 h in total. Overall, the nature of the burden is moderately low.
All the techniques employed are registered for their use and/or routinely
performed at the azM. Outcomes of this study are highly relevant to the
diagnosis and treatment of patients.
*Groepsgebondenheid*. This study must be performed exclusively with the group
of patients who suffer from a psychotic disorder where an autoimmune antibody
might be the cause (*groepsgebondenheid*, article 6 CCMO*). This is especially
true for the subgroup of mentally incompetent (*wilsonbekwame*) patients during
a period with psychosis since the level of antibodies may then be considerably
higher than during stable periods when antibodies can go back to undetectably
low levels. Clearly such cases would be missed if the group of mentally
incompetent patients will not be included. Several cases of autoimmune
encephalitis with antibodies against NMDA receptor and VGKC complex already
point in that direction.