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Olanzapine increases glucogenesis by multiple pathways in brain and muscle

Molecular Psychiatry volume 11, pages 524–525 (2006)Cite this article

Olanzapine is a second generation atypical antipsychotic, with affinity to multiple receptor systems including serotonin, dopamine, muscarinic, adrenergic and histamine H1.1 However, emerging reports indicate that olanzapine's antipsychotic, antidepressant and antimanic effects may be due to its modulation of numerous brain genes/proteins.2 By the same token, some of its side effects such as increased propensity for weight gain may be due to its effects on multiple metabolic genes resident in brain, muscle or liver.2 Recently, Engl et al.3 provided evidence for olanzapine's action on glycogen synthesis and insulin signaling in L6 skeletal muscle cells. These authors showed that acute administration of olanzapine to cultures of L6 rat skeletal muscle cells caused reductions in glycogen content in a dose and time dependent manner. Olanzapine inhibited insulin stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3K activity.3 Additionally, olanzapine diminished phosphorylation of AKT and GSK-3 and increased phosphorylation of glycogen synthase, thereby inhibiting glycogen synthesis.3 These authors concluded that olanzapine inhibits the classical insulin-signalling cascade and that this inhibition may lead to induction of insulin resistance in olanzapine-treated patients.3

Review of data published by Engl et al.3 and those by our laboratory,2 suggests that olanzapine increases glucogenesis in brain and muscle by upregulating glycogen phosphorylase and phosphorylating (inactivating) glycogen synthase in the respective target tissues. The net product of both pathways is increased glucose production, which by necessity leads to increased insulin production and could lead to end-organ insulin resistance. We propose that olanzapine's propensity towards increased glucose production may be of therapeutic relevance, since it provides more energy for local expenditure in brain to improve synaptic transmission in disorders like schizophrenia, depression and manic-depressive illness. Clearly, glucogenesis in brain is, one of several biochemical pathways, used by olanzapine to help in improving synaptic neurotransmission in the diseased brain. Some of the alternative pathways involved in olanzapine's action in brain include upregulation of Reelin mRNA and protein6 and decreases in NMDA3B and RGS2 mRNA and proteins, all leading to improving glutamatergic neurotransmission. Indeed, as shown recently by Lieberman et al.,7 olanzapine and not haloperidol, was capable of diminishing brain gray matter loss in subjects with schizophrenia after a 3 month treatment protocol supporting its beneficial effects in ameliorating cognitive deficits in several psychiatric disorders.

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Figure 1

References

  1. Fatemi SH, Melzer HY . Binding of clanzapine to serotonin receptor subtypes. In: Tran PV et al. (eds). Olanzapine (Zyprexa): A Novel Antipsychotic. Lippincott Williams and Wilkins Healthcare: Philadelphia, PA, 2000, pp. 25–30.

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  2. Fatemi SH et al. Neuropsychopharm 2006, in press.

  3. Engl J et al. Mol Psychiatry 2005; 10: 1089–1096.

  4. Wang H et al. Diabetes 2002; 51: 2861–2865.

  5. Stone WS et al. AmJ Med Genet B Neuropsychiatr Genet 2004; 127: 5–10.

  6. Fatemi SH . Mol Psychiatry 2005; 10: 251–257.

  7. Lieberman JA et al. Arch Gen Psychiatry 2005; 62: 361–370.

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Acknowledgements

The author is grateful to Stanley Medical Research Institute for grant support, Ms T Reutiman and Mr T Folsom for technical help and Ms L Iversen for manuscript preparation.

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  1. Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, Minneapolis, MN, USA

    S H Fatemi

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Fatemi, S. Olanzapine increases glucogenesis by multiple pathways in brain and muscle. Mol Psychiatry 11, 524–525 (2006). https://doi.org/10.1038/sj.mp.4001821

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