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
help identify 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 schizophrenia.
Since cognitive dysfunction is the most disabling and untreatable
characteristic of schizophrenia there is an urgency to look for new potential
therapeutic targets. The M1 receptor is receiving increased interest as a
potential target for the development of cognitive enhancers (36-38). However,
studies testing this hypothesis in-vivo are lacking. Therefore, we wish to
investigate the muscarinic cholinergic system, specifically the M1 receptor,
in-vivo and clinically and neurobiologically characterize a subgroup of
schizophrenia patients using cholinergic markers and specific cognitive tasks.
In order to determine changes in M1 receptors and the modulatory role of
acetylcholine in first episode psychosis patients in cognitive functioning.

The study is a cross-sectional study with a cross-over placebo-controlled arm.
All participants will receive muscarinic SPECT imaging using 123IDEX to assess
M1 binding affinity. 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 fMRI, DTI, and MRS recording 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. Minimal reversible unwanted effects have been found at 4 mg of
biperiden administration (eg. dry mouth, obstipation, concentration
difficulties).

The radiation exposure of the SPECT scan is classified as category IIb
(intermediate), and frequently conducted at the department of nuclear medicine
AMC both in patients as also in healthy human volunteers. Moreover, 123I-IDEX
is a registered radioactive ligand, which is produced routinely according to
GMP-criteria.
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, involving 1 venous puncture for the administration of a
radioligand and cholinergic challenge. The risks involved are negligible as all
the agents and techniques employed are registered for their use and/or
routinely performed at AZM and the AMC. There are indirect benefits for
patients in the study. Outcomes of this study are highly relevant to the
development of new treatments that can treat cognitive impairments in
schizophrenia, thereby substantially improving quality of life of these
patients.