Muscarinic mechanisms of antipsychotic atypicality

Bymaster, Frank P.; Felder, Christian C.; Tzavara, Eleni T.; Nomikos, George G.; Calligaro, David O.; McKinzie, David L.

doi:10.1016/j.pnpbp.2003.09.008

Cited by 128 publications

(98 citation statements)

References 97 publications

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“…Both olanzapine and clozapine are thought to have higher affinity in vitro to various subclasses of serotonin receptors (especially serotonin 1A , 2C ) and cholinergic receptors than conventional antipsychotics. [17][18][19] Olanzapine and clozapine may also stimulate weight gain through activation of hypothalamic AMP increase which may be mediated through actions on histamine H1 receptors. 20 Whether any of these receptor differences are related to the differential effects of the SNPs, we examined on cholesterol and triglycerides in olanzapine and clozapine as compared to those treated with conventional antipsychotics may merit further investigation.…”

Section: Discussionmentioning

confidence: 99%

Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia

et al. 2007

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Schizophrenic patients who are treated with antipsychotics, especially second generation antipsychotics, such as clozapine and olanzapine, manifest an increase in cholesterol and triglycerides as well as other changes associated with diabetes or the metabolic syndrome. Previous studies have shown that polymorphisms in several genes that regulate lipid metabolism can influence the levels of these lipids and response to drug treatment. We have investigated in an exploratory study whether polymorphisms in the apolipoprotein C-III (ApoC3), apolipoprotein A-V gene (ApoA5) and lipoprotein lipase genes influence differential lipid response to treatment with three second generation antipsychotics-olanzapine, clozapine and risperidone-or treatment with a first generation antipsychotic. A total of 189 patients with schizophrenia or schizoaffective disorder who were being treated with a single antipsychotic were studied in a cross-sectional study design in which fasting serum cholesterol and triglycerides and selected single-nucleotide polymorphosms (SNPs) in the three lipid metabolism genes were assessed. The treatment with antipsychotic monotherapy makes drug haplotype ascertainment less complex. Our analyses showed several nominally significant drug Â gene and drug Â haplotype interactions. The rarer C allele or the ApoA5_1131 (T/C) SNP was associated with higher cholesterol levels in patients treated with first generation antipsychotics and lower cholesterol levels in patients treated with olanzapine or clozapine. The rarer C allele of the ApoA5_SW19 (G/C) SNP was associated with higher cholesterol in risperidone-treated patients. An ApoA5 CG haplotype was associated with decreased cholesterol in olanzapine-or clozapine-treated patients and higher cholesterol in patients treated with first generation antipsychotics. The presence of the rarer T allele of the ApoC3_1100 (C/T) SNP or the presence of the ApoC3 TG haplotype was associated with decreased triglyceride levels in patients treated with olanzapine or clozapine and a nonsignificant trend for increased triglycerides in patients treated with first generation antipsychotics. The presence of the ApoC3 CC haplotype was associated with increased triglycerides in patients treated with olanzapine or clozapine. The overall magnitude of the effects was not large. These results provide a potential initial step toward a pharmacogenetic approach to selection of antipsychotic treatment which may help minimize the side effect of increases in serum lipids.

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Section: Discussionmentioning

confidence: 99%

Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia

et al. 2007

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“…Moreover, bipolar adolescents, regardless of remission status, experienced an increase in medial prefrontal gray and right lateral prefrontal white matter choline within the initial week of olanzapine treatment, suggesting that an increase in choline may be an immediate and direct biochemical effect of olanzapine, rather than the result of resolution of manic symptoms. Several investigators have hypothesized involvement of cholinergic neurotransmission in the pathophysiology of bipolar disorder ( Stoll et al, 1991;Bymaster et al, 2003). Indeed, lithium inhibits choline membrane transport and thus leads to an increase in intracellular choline.…”

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

137

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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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“…A further wrinkle in this data is introduced by the fact that both clozapine and olanzapine still release cortical and hippocampal ACh in mice lacking M2 and M4 receptors (Bymaster et al, 2003). As such, neither blockade nor partial agonism at these sites appears to be required for ACh release.…”

Section: A Ach Release Muscarinic Blockade Partial Agonists and "mentioning

confidence: 97%

“…This discrepancy is likely due both to subtype selectivity at muscarinic sites, and to partial agonist activity at M4 and M2 receptors (Bymaster et al, 2003;Michal et al, 1999).…”

Section: A Ach Release Muscarinic Blockade Partial Agonists and "mentioning

confidence: 99%

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

Berman

Talmage

Role

2007

International Review of Neurobiology

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Central cholinergic signaling has long been associated with aspects of memory, motivation, and mood, each affected functions in neuropsychiatric disorders such as schizophrenia. In this chapter, we review evidence related to the core hypothesis that dysregulation of central cholinergic signaling contributes to the pathophysiology of schizophrenia. Although central cholinergic circuits are resistant to simplification-particularly when one tries to parse the contributions of various classes of cholinergic receptors to disease related phenomena-the potential role of ACh signaling in Schizophrenia pathophysiology deserves careful consideration for prospective therapeutics. The established role of cholinergic circuits in attentional tuning is considered along with recent work on how the patterning of cholinergic activity may modulate corticostriatal circuits affected in schizophrenia.

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Muscarinic mechanisms of antipsychotic atypicality

Cited by 128 publications

References 97 publications

Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia

Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia

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

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

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