Diurnal neurobiological alterations after exposure to clozapine in first-episode schizophrenia patients
Abstract
Background Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated.Methods Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin.Results Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin.Conclusion These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia.
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In contrast to melatonin, the cortisol circadian rhythm appears to remain more or less intact in schizophrenia, although concentrations are often elevated relative to healthy controls.
“In contrast to melatonin, the cortisol circadian rhythm appears to remain more or less intact in SZ150–152, although concentrations are often elevated relative to healthy controls156,157.”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [156]
Cites
The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.
Kay, S. R., Fiszbein, A., & Opler, L. A. (1987) · Schizophrenia Bulletin · doi:10.1093/schbul/13.2.261 · Cited by 21,378 · see citing works
Clozapine for the Treatment-Resistant Schizophrenic: A Double-blind Comparison With Chlorpromazine
Kane, J. (1988) · Archives of General Psychiatry · doi:10.1001/archpsyc.1988.01800330013001 · Cited by 4,156 · see citing works
Neurons containing hypocretin (orexin) project to multiple neuronal systems
Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., & Kilduff, T. S. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09996.1998 · Cited by 3,466 · see citing works
Molecular components of the mammalian circadian clock
Ko, C. H., & Takahashi, J. S. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl207 · Cited by 1,657 · see citing works
Date, Y., Ueta, Y., Yamashita, H., Yamaguchi, H., Matsukura, S., Kangawa, K., Sakurai, T., Yanagisawa, M., & Nakazato, M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.2.748 · Cited by 1,050 · see citing works
Melanopsin ( <i>Opn4</i> ) Requirement for Normal Light-Induced Circadian Phase Shifting
Panda, S., Sato, T. K., Castrucci, A. M., Rollag, M. D., DeGrip, W. J., Hogenesch, J. B., Provencio, I., & Kay, S. A. (2002) · Science · doi:10.1126/science.1076848 · Cited by 861 · see citing works
Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia
Walker, E., Mittal, V., & Tessner, K. (2008) · Annual Review of Clinical Psychology · doi:10.1146/annurev.clinpsy.4.022007.141248 · Cited by 615 · see citing works
Leproult, R., Holmbäck, U., & Van Cauter, E. (2014) · Diabetes · doi:10.2337/db13-1546 · Cited by 607 · see citing works
NPAS2: an analog of clock operative in the mammalian forebrain
Reick, M., Garcia, J. A., Dudley, C., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1060699 · Cited by 572 · see citing works
CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock
DeBruyne, J. P., Weaver, D. R., & Reppert, S. M. (2007) · Nature Neuroscience · doi:10.1038/nn1884 · Cited by 484 · see citing works
Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice
Dudley, C. A., Erbel-Sieler, C., Estill, S. J., Reick, M., Franken, P., Pitts, S., & McKnight, S. L. (2003) · Science · doi:10.1126/science.1082795 · Cited by 415 · see citing works
Johansson, C., Willeit, M., Smedh, C., Ekholm, J., Paunio, T., Kieseppä, T., Lichtermann, D., Praschak-Rieder, N., Neumeister, A., Nilsson, L.-G., et al. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300121 · Cited by 341 · see citing works
Mansour, H. A., Wood, J., Logue, T., Chowdari, K. V., Dayal, M., Kupfer, D. J., Monk, T. H., Devlin, B., & Nimgaonkar, V. L. (2006) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2005.00147.x · Cited by 293 · see citing works
Microarray analysis of postmortem temporal cortex from patients with schizophrenia
Aston, C., Jiang, L., & Sokolov, B. P. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20208 · Cited by 283 · see citing works
Mondelli, V., Dazzan, P., Hepgul, N., Di Forti, M., Aas, M., D'Albenzio, A., Di Nicola, M., Fisher, H., Handley, R., Marques, T. R., et al. (2010) · Schizophrenia Research · doi:10.1016/j.schres.2009.08.013 · Cited by 278 · see citing works
Sleep in Untreated Patients With Schizophrenia: A Meta-Analysis
Chouinard, S., Poulin, J., Stip, É., & Godbout, R. (2004) · Schizophrenia Bulletin · doi:10.1093/oxfordjournals.schbul.a007145 · Cited by 275 · see citing works
A prospective study of clozapine in treatment-resistant schizophrenic patients
Meltzer, H. Y., Bastani, B., Kwon, K. Y., et al. (1989) · Psychopharmacology · doi:10.1007/bf00442563 · Cited by 271 · see citing works
Dimensions of Outcome with Clozapine
Meltzer, H. Y. (1992) · The British Journal of Psychiatry · doi:10.1192/s000712500029692x · Cited by 251 · see citing works
Lewis, S. W., Davies, L. M., Jones, P. B., Barnes, T. R. E., Murray, R. M., Kerwin, R. W., Taylor, D. M., Hayhurst, K. P., Markwick, A., Lloyd, H. M., et al. (2006) · Health Technology Assessment · doi:10.3310/hta10170 · Cited by 233 · see citing works
Chronobiology in the endocrine system
Haus, E. L. (2007) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2007.01.001 · Cited by 222 · see citing works
Zhang, X. Y., Zhou, D. F., Cao, L. Y., Wu, G. Y., & Shen, Y. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300756 · Cited by 208 · see citing works
Clock Genes and Clock-Controlled Genes in the Regulation of Metabolic Rhythms
Mazzoccoli, G., Pazienza, V., & Vinciguerra, M. (2012) · Chronobiology International · doi:10.3109/07420528.2012.658127 · Cited by 171 · see citing works
Arranz, B., Rosel, P., Ramírez, N. D., Dueñas, R., Fernández, P., Sanchez, J. M., Navarro, M. A., & San, L. (2004) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v65n1007 · Cited by 161 · see citing works
Mansour, H. A., Talkowski, M. E., Wood, J., Chowdari, K. V., McClain, L., Prasad, K., Montrose, D., Fagiolini, A., Friedman, E. S., Allen, M. H., et al. (2009) · Bipolar Disorders · doi:10.1111/j.1399-5618.2009.00756.x · Cited by 161 · see citing works
Sleep and circadian rhythm dysregulation in schizophrenia
Monti, J. M., BaHammam, A. S., Pandi-Perumal, S. R., Bromundt, V., Spence, D. W., Cardinali, D. P., & Brown, G. M. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.12.021 · Cited by 157 · see citing works
Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia
Rao, M. L., Gross, G., Strebel, B., Halaris, A., Huber, G., Bräunig, P., & Marler, M. (1994) · Biological Psychiatry · doi:10.1016/0006-3223(94)91147-9 · Cited by 154 · see citing works
Lef�bvre, P. J., Paolisso, G., Scheen, A. J., & Henquin, J. (1987) · Diabetologia · doi:10.1007/bf00279610 · Cited by 130 · see citing works
Gonnissen, H. K. J., Rutters, F., Mazuy, C., Martens, E. A. P., Adam, T. C., & Westerterp‐Plantenga, M. S. (2012) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.112.037192 · Cited by 127 · see citing works
Obermeier, M., Mayr, A. J., Schennach-Wolff, R., Seemüller, F., Møller, H. J., & Riedel, M. (2009) · Schizophrenia Bulletin · doi:10.1093/schbul/sbp124 · Cited by 125 · see citing works
van Nimwegen, L. J. M., Storosum, J. G., Blümer, R. M. E., Allick, G., Venema, H. W., de Haan, L., Becker, H. E., van Amelsvoort, T., Ackermans, M. T., Fliers, E., et al. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1167 · Cited by 101 · see citing works
Disturbed Circadian Rest-Activity Cycles in Schizophrenia Patients: An Effect of Drugs?
Wirz‐Justice, A., Haug, H.-J., & Cajochen, C. (2001) · Schizophrenia Bulletin · doi:10.1093/oxfordjournals.schbul.a006890 · Cited by 92 · see citing works
Newer atypical antipsychotic medication versus clozapine for schizophrenia
Tuunainen, A., & Wahlbeck, K. (2000) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000966 · Cited by 85 · see citing works
Nocturnal hormone profiles in patients with schizophrenia treated with olanzapine
Mann, K., Rossbach, W., Müller, M. J., Müller-Siecheneder, F., Pott, T., Linde, I., Dittmann, R. W., & Hiemke, C. (2006) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2005.08.005 · Cited by 78 · see citing works
CLOCK gene T3111C polymorphism is associated with Japanese schizophrenics: A preliminary study
Takao, T., Tachikawa, H., Kawanishi, Y., Mizukami, K., & Asada, T. (2006) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2006.09.002 · Cited by 76 · see citing works
Li, S., Liu, L., Jiang, W., & Lü, L. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06086.x · Cited by 75 · see citing works
Self-citationRao, M. L., Strebel, B., Halaris, A. E., Gross, G., Bräunig, P., Huber, G., & Marler, M. (1995) · Psychiatry Research · doi:10.1016/0165-1781(95)02525-2 · Cited by 73 · see citing works
Li, S., Liu, L.-J., Xu, L., Gao, L., Wang, X., Zhang, J., & Lü, L. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.07.009 · Cited by 71 · see citing works
Self-citationGarner, B., Phassouliotis, C., Phillips, L., Markulev, C., Butselaar, F., Bendall, S., Yun, Y., & McGorry, P. D. (2010) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2010.06.008 · Cited by 70 · see citing works
Naheed, M., & Green, B. (2001) · Current Medical Research and Opinion · doi:10.1185/0300799039117069 · Cited by 70 · see citing works
Naheed, M., & Green, B. (2001) · Current Medical Research and Opinion · doi:10.1185/03007990152673864 · Cited by 66 · see citing works
Circadian Alteration in Neurobiology During 30 Days of Abstinence in Heroin Users
Li, S., Shi, J., Epstein, D. H., Wang, X., Zhang, X.-L., Bao, Y., Zhang, D., Zhang, X., Kosten, T. R., & Lü, L. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.11.025 · Cited by 63 · see citing works
Self-citationChien, Y., Liu, C., Shan, J., Lee, H., Hsieh, M. H., Hwu, H., & Chiou, L. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.12.012 · Cited by 61 · see citing works
Hypocretins (orexins): clinical impact of the discovery of a neurotransmitter
Baumann, C. R., & Bassetti, C. L. (2005) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2005.01.005 · Cited by 57 · see citing works
Matsuda, K., Cho, M. C., Lin, K.-M., et al. (1996) · PubMed · Cited by 56 · see citing works
Circadian alteration in neurobiology during protracted opiate withdrawal in rats
Li, S., Liu, L.-J., Jiang, W., Sun, L., Zhou, S., Foll, B. L., Zhang, X., Kosten, T. R., & Lü, L. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06941.x · Cited by 54 · see citing works
Self-citationWirz‐Justice, A., Werth, E., Savaskan, E., Knoblauch, V., Gasio, P. F., & Müller-Spahn, F. (2000) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-200010000-00005 · Cited by 54 · see citing works
Yeragani, V. K. (1990) · The Canadian Journal of Psychiatry · doi:10.1177/070674379003500204 · Cited by 54 · see citing works
Circadian and Ultradian Rhythms in Blood Glucose and Plasma Insulin of Healthy Adults
Méjean, L., Bicakova-Rocher, A., Kolopp, M., et al. (1988) · Chronobiology International · doi:10.3109/07420528809079564 · Cited by 40 · see citing works
The Pharmacogenetics of Symptom Response to Antipsychotic Drugs
Reynolds, G. P. (2012) · Psychiatry Investigation · doi:10.4306/pi.2012.9.1.1 · Cited by 36 · see citing works
Meltzer, H. Y., Bobo, W. V., Lee, M. A., Cola, P. A., & Jayathilake, K. (2010) · Psychiatry Research · doi:10.1016/j.psychres.2010.02.018 · Cited by 33 · see citing works
A mathematical model of oscillatory insulin secretion
Berman, N., Chou, H.-F., Berman, A., & Ipp, E. (1993) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1993.264.5.r839 · Cited by 17 · see citing works
Cryptochrome1 maybe a candidate gene of schizophrenia
Peng, Z.-W., Chen, X., & Wei, Z. (2007) · Medical Hypotheses · doi:10.1016/j.mehy.2007.02.003 · Cited by 16 · see citing works
Ahlersová, E., Ahlers, I., Šmajda, B., et al. (1992) · PubMed · Cited by 12 · see citing works
Schizophrénie et rythmes circadiens
Vanelle, J. (2009) · L Encéphale · doi:10.1016/s0013-7006(09)75540-x · Cited by 8 · see citing works
Advokat, C. D. (2005) · PubMed · Cited by 7 · see citing works
Horvath (1999) · doi:10.1002/(sici)1096-9861(19991213)415:2
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Circadian rhythm disruption and mental health
Walker, W. H., Walton, J. C., DeVries, A. C., & Nelson, R. J. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0694-0 · Cited by 1,030 · see citing works
Disrupted sleep and circadian rhythms in schizophrenia and their interaction with dopamine signaling
Ashton, A., & Jagannath, A. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00636 · Cited by 106 · see citing works
- Authors
- Sun, H.-Q., Li, S.-X., Chen, F.-B., Zhang, Y., Li, P., Jin, M., Sun, Y., Wang, F., Mi, W.-F., Shi, L., Yue, J.-L., Yang, F.-D., & Lu, L.
- Affiliations
- Peking University (CN)
- Chinese People's Liberation Army (CN)
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 64
- Pages
- 108-116
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W2176975430
- Cited by
- 42
- References
- 56
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 7 · 2020: 5 · 2019: 7 · 2018: 2 · 2017: 3 · 2016: 1
- FWCI
- 1.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of China (81271475, 81571297, 81171251, 81221002)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, clozapine, circadian rhythm, clock genes, Per1, Per2, Per3, NPAS2, orexin, cortisol, insulin, first-episode schizophrenia, antipsychotic drugs, maintenance therapy
- MeSH terms
- Orexins, Adolescent, Adult, Circadian Rhythm, Clozapine, Humans, Hydrocortisone, Insulin, Male, Middle Aged, Nerve Tissue Proteins, Schizophrenia, Time Factors, Case-Control Studies, Basic Helix-Loop-Helix Proteins, Young Adult, Period Circadian Proteins
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