Schizophrenia and MUscarinic Receptor Functioning

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.



45 first episode psychosis patients 18 years of age and older will be recruited and these will be matched with 45 healthy control subjects. All participants will be mentally competent to assess participation. Only the patients will undergo SPECT imaging.

It is hypothesized that:

-there will be a subgroup of patients with first episode psychosis with reduced Muscarinic M1 receptor binding.

-The patients with reduced M1 receptor binding will perform significanlty worse on a cognitive test battery (CANTAB) than the patients without reduced M1 binding

-The patients with reduced M1 receptor binding will have decreased hippocampal and prefrontal activation response to the cholinergic challenge biperiden during a fMRI visual learning & memory ans a social cognition task than the patients without reduced M1 receptor binding and healthy controls.

All Participants will undergo two MRI scanning sessions with cognitive tasks- once under a cholinergic challenge with biperiden, and once after receiving a placebo. Time-inteval between testdays will be at least one week.

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.