Effects of anticholinergic challenge on psychopathology and cognition in drug-free patients with schizophrenia and healthy volunteers

Veselinović, Tanja; Vernaleken, Ingo; Janouschek, Hildegard; Kellermann, Thilo; Paulzen, Michael; Cumming, Paul; Gründer, Gerhard

doi:10.1007/s00213-014-3794-9

Cited by 17 publications

(10 citation statements)

References 49 publications

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“…Consequently, lower M 1 density in the DLPFC may be associated with worse verbal learning and memory performance. These findings are compatible with improvements in verbal learning and memory found under M 1/4 agonism by xanomeline in patients with schizophrenia, and deficits in verbal learning and memory found under antagonism by biperiden, which has a 10 fold higher affinity for the M 1 receptor over the other subtypes, in both healthy controls and psychotic disorders ( Shekhar et al, 2008 ; Veselinović et al, 2015 ). Although 123 I-IDEX in in-vitro studies also shows a relatively high affinity for the M 4 subtype, expression rates of M 4 in the DLPFC of humans are low and preclinical studies showed no changes in 123 I-IDEX binding in the frontal cortex of M 4 knock-out mice, suggesting preferential binding of 123 I-IDEX to M 1 receptors in this brain area ( Bakker et al, 2015 ).…”

Section: Discussionsupporting

confidence: 81%

Relationship between muscarinic M1 receptor binding and cognition in medication-free subjects with psychosis

Bakker

Vingerhoets

Boucherie

et al. 2018

NeuroImage: Clinical

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BackgroundIt is still unclear which underlying mechanisms are involved in cognitive deficits of psychotic disorders. Pro-cognitive effects of muscarinic M1 receptor agonists suggest alterations in M1 receptor functioning may modulate these symptoms. Post mortem studies in patients with schizophrenia have shown significantly reduced M1 receptor expression rates in the dorsolateral prefrontal cortex (DLPFC) compared to controls. To date no in-vivo examinations of M1 receptor binding in relation to cognitive impairments have been done. As cognitive deficits have similar course and prognostic relevance across psychotic disorders, the current study assessed M1 receptor binding in the DLPFC and hippocampus in relation to cognitive functioning.MethodsMuscarinic M1 receptor binding potential (BPND) was measured using 123I-IDEX, single photon emission computed tomography (SPECT) in 30 medication-free subjects diagnosed with a psychotic disorder. A computerized neuropsychological test battery was used to assess cognition, and the positive and negative syndrome scale (PANSS) to assess severity of psychotic symptoms.ResultsAssessment of cognitive domains showed that lower M1 BPND in the DLPFC was related to overall lower performance in verbal learning and memory. In addition, lower M1 BPND in the DLPFC was related to greater negative symptom severity. Lastly, lower M1 BPND in the hippocampus was related to worse delayed recognition of verbal memory.ConclusionThis is the first study to show that variation in M1 receptors in the DLPFC is related to cognitive and negative symptom outcome in psychotic disorders. The M1 receptor may be an important biomarker in biological stratification of patients with psychotic disorders.

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Section: Discussionsupporting

confidence: 81%

Relationship between muscarinic M1 receptor binding and cognition in medication-free subjects with psychosis

Bakker

Vingerhoets

Boucherie

et al. 2018

NeuroImage: Clinical

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“…However, their usage has often been questioned as they themselves cause a range of side-effects, such as cognitive impairment, tardive dyskinesia, blurred vision, dry mouth, problems with urinary retention, psychosis, addiction, and many more ( 30 – 32 ). To give an example, Veselinović et al ( 33 ) investigated the effect of the administration of anticholinergics on cognition in untreated patients with schizophrenia and healthy control subjects. Their results showed a marked impairment in both groups, which was however more pronounced in the schizophrenia patients, thus again casting doubt on the suitability of these drugs in the treatment of schizophrenia ( 33 ).…”

Section: Antimuscarinic Drugsmentioning

confidence: 99%

“…To give an example, Veselinović et al ( 33 ) investigated the effect of the administration of anticholinergics on cognition in untreated patients with schizophrenia and healthy control subjects. Their results showed a marked impairment in both groups, which was however more pronounced in the schizophrenia patients, thus again casting doubt on the suitability of these drugs in the treatment of schizophrenia ( 33 ).…”

Section: Antimuscarinic Drugsmentioning

confidence: 99%

“…As mentioned previously, mAChR antagonists (e.g., biperiden, trihexyphenidyl) are also employed as prophylaxis and/or for the treatment of side-effects of antipsychotics prescribed in diseases such as schizophrenia. However, this method is currently on the decline due to the multitude of unwanted side-effects of the anticholinergic treatment ( 30 , 33 ).…”

Section: Antimuscarinic Drugsmentioning

confidence: 99%

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Drugs Interfering with Muscarinic Acetylcholine Receptors and Their Effects on Place Navigation

2017

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Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, ranging from motivation and feeding to spatial navigation, an important and widely studied type of cognitive behavior. Systemic administration of non-selective antagonists of mAChRs, such as scopolamine or atropine, have been found to have adverse effects on a vast majority of place navigation tasks. However, many of these results may be potentially confounded by disruptions of functions other than spatial learning and memory. Although studies with selective antimuscarinics point to mutually opposite effects of M1 and M2 receptors, their particular contribution to spatial cognition is still poorly understood, partly due to a lack of truly selective agents. Furthermore, constitutive knock-outs do not always support results from selective antagonists. For modeling impaired spatial cognition, the scopolamine-induced amnesia model still maintains some limited validity, but there is an apparent need for more targeted approaches such as local intracerebral administration of antagonists, as well as novel techniques such as optogenetics focused on cholinergic neurons and chemogenetics aimed at cells expressing metabotropic mAChRs.

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“…Because of the higher M 1 selectivity of biperiden, a biperiden challenge model would be more appropriate to use in early phase clinical studies of M 1 specific mAChR agonists. Several studies have investigated biperiden as a cognitive challenge model in healthy young [12][13][14][15][16] , healthy elderly 11 , and schizophrenia patients 10 .…”

Section: Introductionmentioning

confidence: 99%

Biperiden Challenge Model in Healthy Elderly as Proof‐of‐Pharmacology Tool: A Randomized, Placebo‐Controlled Trial

Bakker

Esdonk

Stuurman

et al. 2021

The Journal of Clinical Pharma

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Selective M 1 muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition enhancing effects in early phase clinical development in healthy subjects is difficult. A challenge with the M 1 mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M 1 mAChR agonists. The aim of this study was to develop such a model. To this end, twelve healthy elderly subjects participated in a randomized, placebo controlled, three-way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK-PD model was developed. Four mg biperiden showed significant impairment of sustained attention (-2.1% point in adaptive tracking (95% CI [-3.043; -1.148])), verbal memory (2-3 words fewer recalled (95% CI [-5.9; -0.2])), and working memory (up to 50 ms increase in the n-back task reaction time (95% CI [21.854; 77.882])) compared with placebo. The PK data was best fitted by a 2-compartment model and showed a high inter-occasion and inter-subject variability. Population PK-PD analysis quantified significant concentration-effect relationships for the n-back reaction times, n-back accuracies and adaptive tracking. In conclusion, biperiden caused M 1 mAChR related doseand concentration-dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof-of-pharmacology studies and to demonstrate cognition enhancing effects of new cholinergic compounds that are being developed.

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Effects of anticholinergic challenge on psychopathology and cognition in drug-free patients with schizophrenia and healthy volunteers

Cited by 17 publications

References 49 publications

Relationship between muscarinic M1 receptor binding and cognition in medication-free subjects with psychosis

Relationship between muscarinic M1 receptor binding and cognition in medication-free subjects with psychosis

Drugs Interfering with Muscarinic Acetylcholine Receptors and Their Effects on Place Navigation

Biperiden Challenge Model in Healthy Elderly as Proof‐of‐Pharmacology Tool: A Randomized, Placebo‐Controlled Trial

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