Clinical and neurobiological characterisation of "muscarinic receptor-deficit schizophrenia" (MRDS)

Schizophrenia is a serious chronic disorder, usually starting in adolescence.
Currently available treatments show no therapeutic effects on cognitive
dysfunction, one of the most disabling characteristics of the disease.
Cognitive impairment is a predictor of functional outcome and thus pertinent to
successful treatment paradigms. Post mortem studies have found evidence of
changes in acetylcholine neurotransmission at the muscarinic (M1) receptor,
both in the frontal cortex and hippocampal regions of the brain, associated
with cognitive functioning in both healthy control subjects and schizophrenia.
Results from a hallmark post-mortem study identified a subgroup of patients
among schizophrenia with *muscarinic receptor-deficit schizophrenia (MRDS)*
with up to 75% loss of muscarinic receptors. It is not known whether MRDS
patients present schizophrenia-associated cognitive deficits. This study will
test the hypothesis that MRDS can be identified in-vivo and that clincal and
neurobiological characteresation of this group of patients will help
identifying the neurobiological basis of cognitive impairments in
schizophrenia.

The main objective of the study is to investigate the muscarinic cholinergic
system as a biological substrate for cognitive dysfunction in first episode
psychosis patients, i.e. at onset of illness. We seek to assess whether
deficits in M1 cholinergic neurotransmission exist at onset psychosis and if
there is dissociation between MRDS patients, with significantly lower M1
binding, and non*MRDS patients. Furthermore, M1 bindingpotential in these
regions will be related to cognitive functioning. The modulatory role of
acetylcholine at M1 and differentiation in functional activation patterns will
be assessed in comparison to healthy control subjects in verbal learning and
memory and social cognition.

The study is a single-blind, cross-sectional placebo-controlled study. Only the
first episode psychosis patients will receive SPECT imaging using 123I-IDEX on
one occasion to assess brain M1 receptor binding. All Participants will then
undergo two MRI scanning sessions with cognitive tasks- once under a
cholinergic challenge with biperiden, and once after receiving a placebo.

On two occasions non- invasive 3.0 Tesla MRI recordings will be conducted
following a single dose of 4 mg biperiden or placebo, administered orally. For
the SPECT study a registered, well- validated radioligand 123I-IDEX will be
administered intravenously.

No serious side effects are foreseen. MRI is a non-invasive measuring
apparatus. Mild reversible unwanted effects have been found at 4 mg of
biperiden administration (eg. dry mouth, obstipation, concentration
difficulties) but these are transient if occur.
The radiation exposure of the SPECT scan is classified as category IIb
(intermediate), and frequently conducted at the department of nuclear medicine
AMC. Moreover, 123I-IDEX will be produced according to GMP-z criteria quality
benchmark.

The nature of the burden is classified as moderate considering that subjects
will have to come to the AMC on 2 different occasions, undergo 2 different
types of scans. For the SPECT scan the nature of the burden is 1 venous
puncture and for the MRI scan participants will be given biperiden orally as
cholinergic challenge. For the healthy control subjects, the burden is
considered low given that they only undergo 1 type of scan (MRI). The risks
involved are negligible as all the agents and techniques employed are
registered for their use and/or routinely performed at the AMC. Potential
unwanted effects are mild and transient. The study will be conducted at all
times under direct supervision of physicians. There are indirect benefits for
patients in the study.