MHENS School for Mental Health and Neuroscience

The influence of a muscarinic M1 receptor antagonist on brain choline levels in patients with a psychotic disorder and healthy controls.

W.A.M. VingerhoetsA,B, G. BakkerA,B, O. BloemenA,C, M. CaanD, J. BooijB, T.A.M.J. van AmelsvoortA.

A Department of Psychiatry & Psychology, Maastricht University, Maastricht, The Netherlands.. B Department of Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands. C GGZ Centraal, Center for Mental Health Care, Hilversum, The Netherlands D Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands

Background • The majority of the patients with a psychotic disorder report cognitive impairments in addition to positive and negative symptoms.

• It is well known that the neurotransmitter acetylcholine plays an important role in cognition. • A post-mortem study of chronic schizophrenia patients demonstrated a reduction of up to 75% in the number of the acetylcholine muscarinic M1 receptors (1).

• Research has shown that muscarinic cholinergic receptors play a major role in cognitive processes.

Objective

• To investigate in-vivo whether there are differences in baseline choline levels in the anterior cingulate cortex (ACC) and striatum between recent onset medication-free patients with a psychotic disorder and healthy control subjects.

• To investigate in-vivo the influence of a muscarinic antagonist on choline

levels in the ACC and striatum in recent onset medication-free patients with Figure 2. Example of a striatal spectrum. a psychotic disorder and healthy control subjects.

Results

Methods • No significant differences were found in baseline choline levels between the two groups in both the striatum (p=0.336) and the ACC (p=0.479). • 20 medication-free patients with a psychotic disorder and 27 healthy

controls were included.

0.30 0.35

• The patient group included 15 males and 5 females with a mean age of 27 . 0.30 years. The HC group included 15 males and 12 females with a mean age of 0.25 25 years. 0.25

0.20 • The two groups were matched for demographic variables. 0.20

0.15 • Choline (precursor for acetylcholine) concentrations were obtained using 0.15 HC HC

3Tesla Magnetic Resonance Spectroscopy (MRS, PRESS). (Ch0/Cre) levels choline ACC Baseline (Cho/Cre) levels choline striatal Baseline Psychosis Psychosis

• Choline concentrations were measured twice: once after placebo and once • A significant main effect of biperiden was found in the striatum (p= 0.024), as after oral administration of 4mg. biperiden. well as an interacation effect of biperiden x age (p= .039). No group differences were found (p= .340). • Biperiden is a selective M1 receptor antagonist. • However, biperiden did not have a significant effect on choline concentrations • Participants were scanned 90 minutes after administration of biperiden. in the ACC (p= 0.634). No group differences were found (p= 0.856) in this region. • The order of placebo and biperiden was counterbalanced. 0.27 HC 0.26 HC Psychosis Psychosis • A repeated measures Analysis of Covariance (ANCOVA) was conducted with 0.26 0.25 age and gender as covariates. 0.24 0.25

0.23 0.24

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0.22 Striatal Choline levels Choline Striatal 0.21 the ACC in levels Choline 0.22

Placebo Placebo Biperiden Biperiden

Conclusion • The lack of differences in choline concentrations between the two groups suggests that there are no alterations in choline concentrations or the Figure 1. Voxel location. The red box indicates the voxel location for the ACC and the blue box degrading of acetylcholine into choline in psychosis. indicates the voxel location for the striatum. • The interaction we found between biperiden and age is in line with findings of decreased M1 receptor expression with increasing age. References • Biperiden significantly increases concentrations of free choline in the striatum 1. Scarr, E., Cowie, T.F., Kanellakis, S., Sundram, S., Pantelis, C., Dean, B., 2009. Decreased cortical and therefore is a suitable challenge to investigate the relation between M1 muscarinic receptors define a subgroup of subjects with schizophrenia. Molecular Psychiatry 14, 1017–23. receptor expression and cognitive functioning.

Correspondence to:

Dept of Psychiatry & Psychology Maastricht University Claudia Vingerhoets T +43 388 3928 P.O. Box 616 [email protected] F +43 388 4122 6200 MD Maastricht, The Netherlands