In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia

Raedler, Thomas J.; Knable, Michael B.; Jones, Douglas W.; Lafargue, Todd; Urbina, Richard A; Egan, Michael; Pickar, David; Weinberger, Daniel R.

doi:10.1016/s0893-133x(99)00162-1

Cited by 74 publications

(37 citation statements)

References 41 publications

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“…Since acetylcholine plays an important role in various domains of cognition including attention, it seems reasonable to suggest that changes in the muscarinic receptor system in the ACC in schizophrenia may be involved in the pathology of the disorder, particularly in relation to attentional and cognitive deficits. Most of the atypical antipsychotic drugs (eg clozapine, olanzapine) used for the treatment of both positive and negative symptoms of schizophrenia with less incidence of extrapyramidal side effects have been shown to possess muscarinic antagonistic properties (Raedler et al, 2000). Therefore, abnormalities in the muscarinic receptor system in the ACC in schizophrenia may also be involved in the pharmacotherapy of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, muscarinic receptorcoupled pertussis toxin-sensitive G proteins have been suggested to be the molecular site for the antimanic therapeutic effects of antibipolar treatments (Avissar and Schreiber, 1991). Atypical antipsychotic drugs (eg clozapine, olanzapine), which are among the most effective anti-schizophrenia medications available, have strong antimuscarinic properties (Raedler et al, 2000). Further, studies using post-mortem brain tissue suggest regionspecific changes to muscarinic receptors in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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Investigation of M1/M4 Muscarinic Receptors in the Anterior Cingulate Cortex in Schizophrenia, Bipolar Disorder, and Major Depression Disorder

Zavitsanou

Katsifis

Mattner

et al. 2003

Neuropsychopharmacol

130

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Abnormal cholinergic neurotransmission has been suggested to occur in psychiatric illness. Therefore, this study investigated cholinergic muscarinic receptors in the anterior cingulate cortex (ACC) of schizophrenia, bipolar disorder and major depression disorder (n ¼ 15 per group). We used quantitative autoradiography to measure [ 3 H]pirenzepine binding to M1 and M4 receptors. Brain tissue was obtained from the Stanley Foundation Neuropathology Consortium. [ 3 H]pirenzepine binding was higher in superficial laminae (I-II) than in deep laminae (III-VI) of the ACC. There was a significant 24% reduction in the density of [ 3 H]pirenzepine in the deep laminae and a significant 19% reduction in the upper laminae of the ACC in the schizophrenia group compared to the control group. There were no differences in [ 3 H]pirenzepine binding in any laminae of the ACC in the bipolar or major depression groups compared with the control group, except for a trend towards decreased [ 3 H]pirenzepine binding in subjects with major depression relative to control subjects. We also detected a significant effect of suicide on [ 3 H]pirenzepine binding in the ACC in subjects who died as a result of suicide relative to those who did not, which was more evident in patients with schizophrenia. A significant effect of the onset of the disease was also observed that was more evident in patients with bipolar disorder. The study provides evidence of decreased muscarinic receptor density in the ACC in schizophrenia but no evidence for significant changes in these receptors in the bipolar and major depression groups. The changes observed in schizophrenia may contribute to dysfunctional ACC neural circuits.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Investigation of M1/M4 Muscarinic Receptors in the Anterior Cingulate Cortex in Schizophrenia, Bipolar Disorder, and Major Depression Disorder

Zavitsanou

Katsifis

Mattner

et al. 2003

Neuropsychopharmacol

130

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“…Results from prior studies demonstrate that olanzapine has a high affinity for muscarinic receptors, specifically the M2 autoreceptor (Raedler et al, 2000), and increases acetylcholine release in prefrontal regions (Ichikawa et al, 2002), which may lead to increases in choline. Choline is also precursor and metabolite of membrane phospholipids, such as phosphatidylcholine.…”

Section: Discussionmentioning

confidence: 99%

Neurochemical Effects of Olanzapine in First-Hospitalization Manic Adolescents: A Proton Magnetic Resonance Spectroscopy Study

DelBello

Cecil

Adler

et al. 2005

Neuropsychopharmacol

114

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We used proton magnetic resonance spectroscopy ( 1 H MRS) to compare the in vivo effects of olanzapine on prefrontal N-acetylaspartate (NAA) levels in treatment remitters and nonremitters. Secondary aims of this study were to identify neurochemical predictors of successful olanzapine treatment and other neurochemical effects of olanzapine. In all, 20 adolescents admitted for their first hospitalization for bipolar disorder, type I, manic or mixed and 10 demographically matched healthy subjects were recruited. Manic adolescents were treated with olanzapine monotherapy and scanned at three time points (N ¼ 19). Medial and left and right lateral ventral prefrontal NAA, choline, creatine/phosphocreatine, myo-inositol, and glutamate/glutamine were measured at baseline, prior to receiving medication, and on days 7 and 28 of treatment. Healthy subjects did not receive medication but underwent 1 H MRS scans at the same time points to assess for normal variability in metabolites over time. Although there was no overall increase in NAA in manic adolescents following 28 days of treatment with olanzapine, olanzapine remitters (N ¼ 11, 58%) exhibited a greater increase in medial ventral prefrontal NAA compared with nonremitters (N ¼ 8, 42%, p ¼ 0.006). Specifically, from baseline to end point, NAA levels decreased in nonremitters (p ¼ 0.03) and increased in remitters (p ¼ 0.05). Manic adolescents treated with olanzapine had an increase from baseline to day 7 in medial (p ¼ 0.002) and right lateral (p ¼ 0.02) ventral prefrontal choline. Baseline medial ventral prefrontal choline was greater in olanzapine remitters than in nonremitters (p ¼ 0.001). Successful treatment of mania with olanzapine may lead to increased ventral prefrontal neuronal viability and/or function as compared to unsuccessful treatment with olanzapine. Additionally, olanzapine-induced increases in choline may lead to alteration of abnormalities in cell membrane metabolism or second messenger pathways that are thought to be involved in the pathophysiology of bipolar disorder.

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“…At a daily dose of 20 mg of olanzapine, the muscarinic receptor occupancy was estimated to be 28% in the basal ganglia and 38% in the cortex. 98 In another study using [I-123]-iododexetimide, a different SPECT-ligand for the muscarinic receptors, a substantial occupancy of the muscarinic receptors was confirmed in the striatum and cortex after treatment with olanzapine. 99 Both studies found no relationship between muscarinic receptor availability and side effects.…”

Section: Neuroimaging Studiesmentioning

confidence: 97%

Towards a muscarinic hypothesis of schizophrenia

Raedler

Bymaster

Tandon³

et al. 2006

Mol Psychiatry

247

211

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Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including preclinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.

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In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia

Abstract: Olanzapine is an atypical antipsychotic with potent antimuscarinic properties in vitro (K i ϭ 2-25 nM

Cited by 74 publications

References 41 publications

Investigation of M1/M4 Muscarinic Receptors in the Anterior Cingulate Cortex in Schizophrenia, Bipolar Disorder, and Major Depression Disorder

Investigation of M1/M4 Muscarinic Receptors in the Anterior Cingulate Cortex in Schizophrenia, Bipolar Disorder, and Major Depression Disorder

Neurochemical Effects of Olanzapine in First-Hospitalization Manic Adolescents: A Proton Magnetic Resonance Spectroscopy Study

Towards a muscarinic hypothesis of schizophrenia

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