Weiner DM, Meltzer HY, Veinbergs I, Donohue EM, Spalding TA, Smith TT et al. The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology 177: 207-216

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Psychopharmacology (Impact Factor: 3.88). 01/2005; 177(1-2):207-16. DOI: 10.1007/s00213-004-1940-5
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Clozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described.
To comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay.
Profiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone.
The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

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    • "en these two loca - tions were not obvious and therefore we refrained from a statistically evaluation . Altered mAChR function related to the individual history of seizures or medications cannot be evaluated in the relatively small cohort of patients but appears unlikely considering similar pharmacology to human recep - tors in expression system ( Weiner et al . 2004 ) . Also gross changes in the pharmacological properties of mAChRs appear unlikely since several other ligands at mAChRs ( CCh , AFDX , atropine , pirenzepine ) had a qualitatively similar effect in human and rats ( Thomas et al . 2010 ; Gigout et al . 2012a , b ) . Conceivably M 2 and M 4 mAChRs of rat and human neurons exhibit subtle "
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    ABSTRACT: Cholinergic transmission plays a pivotal role in learning, memory and cognition, and disturbances of cholinergic transmission have been implicated in neurological disorders including Alzheimer's disease, epilepsy and schizophrenia. Pharmacological alleviation of these diseases by drugs including N-desmethylclozapine (NDMC), promising in animal models, often fails in patients. We therefore compared the effects of NDMC on glutamatergic and GABAergic transmission in slices from rat and human neocortex. We used carbachol (CCh; an established agonist at metabotropic muscarinic acetylcholine (ACh) receptors (mAChRs)) as a reference. Standard electrophysiological methods including intracellular and field potential recordings were used. In the rat neocortex, NDMC prevented the CCh-induced decrease of GABAA and GABAB receptor-mediated responses but not the CCh-induced increase of the paired-pulse depression. NDMC reduced neither the amplitude of the excitatory postsynaptic potentials (EPSP) nor antagonized the CCh-induced depression of EPSP. In the human neocortex, however, NDMC failed to prevent CCh-induced decrease of the GABAB responses and directly reduced the amplitude of EPSP. These data suggest distinct effects of NDMC in rat and human at M2 and M4 mAChRs underlying presynaptic modulation of GABA and glutamate release, respectively. In particular, NDMC might be a M2 mAChR antagonist in the rat but has no activity at this receptor in human neocortex. However, NDMC has an agonistic effect at M4 mAChR in the human but no such effect in the rat neocortex. The present study confirms that pharmacology at mAChRs can differ between species and emphasizes the need of studies in human tissue.
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    • "To date, no drugs have been approved for treating negative symptoms or cognitive dysfunction in schizophrenia (Floresco et al., 2005; Geyer, 2010). Although there has evidence for modest antipsychotic-induced improvement in cognition (Bilder et al., 2002; Weiss et al., 2002; Weiner et al., 2004; Keefe et al., 2007), several investigators and clinicians have questioned the real-world clinical relevance of these effects. For example, antipsychotic-induced improvement of patients' ability to recall a 12-word list by a tenth of a word, while statistically significant (Keefe et al., 2007), may not be clinically meaningful (Heinrichs, 2007). "
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    • "Muscarinic M 1 agonism may improve cognition, whereas antimuscarinic activity potentially worsens cognitive function. Therefore, the effects of clozapine depend on a balance between the plasma and brain concentration of the compound (Weiner et al., 2004; Didriksen et al., 2007). The antihistaminergic effects of olanzapine (Arnt and Skarsfeldt, 1998; Schotte et al., 1996) may also influence cognitive performance. "
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