Melatonin as a Biological Marker in Schizophrenia

  • Armando L. Morera
  • Pedro Abreu-Gonzalez
  • Manuel Henry

It is widely accepted that schizophrenia is not a single disease but different subgroups of biological and clinically heterogeneous entities. There are no routine laboratory tests that could help clinicians in its diagnosis as in other diseases. The association between pineal gland and mental functions stems from Descartes. Melatonin is the main hormone of the pineal gland. The use of melatonin as a possible marker in schizophrenia has gone parallel with the development of laboratory techniques. It is not until the late seventies of the past century that such techniques were generalised. A common drawback of researching on this topic consists of studying melatonin levels in schizophrenic patients without having a clear hypothesis that would have had linked their results with the pathophysiology of schizophrenia. In this chapter the biosynthesis, receptor subtypes and functions of melatonin are highlighted and especially the role of melatonin as a possible biological marker in schizophrenia is reviewed. General research in this topic lacks of homogeneity concerning researching methodology. Several recommendations are made when researching in this area. Clear conclusions are drawn regarding the results from studies relating melatonin to schizophrenia. With the recent advent of new dregs targeting melatonin receptors we will assist to an explosion affecting basic as well as clinical research, rendering plausible important applications in the near future.


Schizophrenia melatonin pineal gland biological markers 


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  1. 1.
    Sadock BJ, Sadock VA. Schizophrenia. In: Sadock BJ, Sadock VA (eds) Kaplan & Sadock's Synopsys of Psychiatry, 10th ed. Lippincott Williams & Wilkins, Baltimore, MD; 2007;467–497Google Scholar
  2. 2.
    Mullen PE, Silman RE. The pineal and psychiatry: a review. Psychol Med 1977;7:407–417PubMedGoogle Scholar
  3. 3.
    Becker WH. Epiglandol bei dementia praecox. Therapeust Halbmonast 1920;34:667–668Google Scholar
  4. 4.
    Hofman MA, Skene DJ, Swaab DF. Effect of photoperiod on the diurnal melatonin and 5-methoxytryptophol rhythms in the human pineal gland. Brain Res 1995;671:254–260PubMedGoogle Scholar
  5. 5.
    Lynch HJ, Ozaki Y, Wurtman RJ. The measurement of melatonin in mammalian tissues and body fluids. J Neural Transm 1978;Suppl 13:251–264Google Scholar
  6. 6.
    Lewy AJ, Markey SP. Analysis of melatonin in human plasma by gas chromatography negative chemical ionization mass spectrometry. Science 1978;201:741–743PubMedGoogle Scholar
  7. 7.
    Thoresen TS. Radioimmmunoassay for melatonin in human serum. Scand J Clin Lab Invest 1978;38:687–692PubMedGoogle Scholar
  8. 8.
    Smith JA, Mee TJX, Barnes JLC. Elevated melatonin serum concentrations in psychiatric patients treated with chlorpro-mazine. J Pharm Pharmacol 1977;Suppl. 29:30PGoogle Scholar
  9. 9.
    Smith JA, Mee TJ, Barnes JD. Increased serum melatonin levels in chlorpromazine-treated psychiatric patients. J. Neural Transm 1978;Suppl 13:397Google Scholar
  10. 10.
    Smith JA, Barnes JL, Mee TJ. The effect of neuroleptic drugs on serum and cerebrospinal fluid melatonin concentrations in psychiatric subjects. J Pharm Pharmacol 1979;31:246–248PubMedGoogle Scholar
  11. 11.
    Ferrier IN, Johnstone EC, Crow TJ, et al. Melatonin/cortisol ratio in psychiatric illness. Lancet 1982;8:1070Google Scholar
  12. 12.
    Ferrier IN, Arendt J, Johnstone EC, et al. Reduced nocturnal melatonin secretion in chronic schizophrenia: relationship to body weight. Clin Endocrinol (Oxf) 1982;17:181–187Google Scholar
  13. 13.
    Fanget F, Claustrat B, Dalery J, et al. Nocturnal plasma melatonin levels in schizophrenic patients. Biol Psychiatry 1989;25:499–501PubMedGoogle Scholar
  14. 14.
    Rao ML, Gross G, Strebel B, et al. Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects. Psychiatry Res 1990;34:243–257PubMedGoogle Scholar
  15. 15.
    Monteleone P, Maj M, Fusco M, et al. Depressed nocturnal plasma melatonin levels in drug-free paranoid schizophrenics. Schizophr Res 1992;7:77–84PubMedGoogle Scholar
  16. 16.
    Monteleone P, Natale M, La Rocca A, et al. Decreased nocturnal secretion of melatonin in drug-free schizophrenics: no change after subchronic treatment with antipsychotics. Neuropsycho-biology 1997;36:159–163Google Scholar
  17. 17.
    Jiang HK, Wang J Y. Diurnal melatonin and cortisol secretion profiles in medicated schizophrenic patients. J Formos Med Assoc 1998;97:830–837PubMedGoogle Scholar
  18. 18.
    Vigano D, Lissoni P, Rovelli F, et al. A study of light/dark rhythm of melatonin in relation to cortisol and prolactin secretion in schizophrenia. Neuro Endocrinol Lett 2001;22:137–141PubMedGoogle Scholar
  19. 19.
    Bersani G, Mameli M, Garavini A, et al. Reduction of night/ day difference in melatonin blood levels as a possible disease-related index in schizophrenia. Neuro Endocrinol Lett 2003;24:181–184PubMedGoogle Scholar
  20. 20.
    Beckmann H, Wetterberg L, Gattaz WF. Melatonin immu-noreactivity in cerebrospinal fluid of schizophrenic patients and healthy controls. Psychiatry Res 1984;11:107–110PubMedGoogle Scholar
  21. 21.
    Rao ML, Gross G, Strebel B, et al. Circadian rhythm of tryp-tophan, serotonin, melatonin, and pituitary hormones in schizophrenia. Biol Psychiatry 1994;35:151–163PubMedGoogle Scholar
  22. 22.
    Mann K, Rossbach W, Muller MJ, et al. Nocturnal hormone profiles in patients with schizophrenia treated with olanzapine. Psychoneuroendocrinology 2006;31:256–264PubMedGoogle Scholar
  23. 23.
    Morera A, Henry M, Abreu P, et al. Melatonin therapeutic use in psychiatry: a 39 year bibliographic study. Actas Esp Psiquiatr 2006;34:344–351PubMedGoogle Scholar
  24. 24.
    Ebadi M. Regulation of the synthesis of MLT and its significance to neuroendocrinology. In: Reiter RJ (ed.) The Pineal Gland. Raven Press, New York, 1984;1–38Google Scholar
  25. 25.
    Zimmermann RC, McDougle CJ, Schumacher M, et al. Effects of acute tryptophan depletion on nocturnal MLT secretion in humans. J Clin Endocrinol Metab 1993;76: 1160–1164PubMedGoogle Scholar
  26. 26.
    Underwood H. The pineal and melatonin: regulators of cir-cadian function in lower vertebrates. Experientia 1990;46: 120–128PubMedGoogle Scholar
  27. 27.
    Hall JC. Cycling transcript and the circadian clock. Curr Biol 1991;1:89–90PubMedGoogle Scholar
  28. 28.
    Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocrine Rev 1991;12:151–180Google Scholar
  29. 29.
    Sugden D. Melatonin biosynthesis in the mammalian pineal gland. Experientia 1989;45:922–932PubMedGoogle Scholar
  30. 30.
    Cardinali DP, Lynch HJ, Wurtman RJ. Binding of melatonin to human and rat plasma protein. Endocrinology 1972;91:1213–1218PubMedGoogle Scholar
  31. 31.
    Mallo C, Zaidan R, Galy G, et al. Pharmacokinetics of MLT in man after intravenous infusion and bolus injection. Eur J Clin Pharmacol 1990;38:297–301PubMedGoogle Scholar
  32. 32.
    Arendt J. Melatonin and the Mammalian Pineal Gland. Chapman & Hall, London, 1995Google Scholar
  33. 33.
    Viljoen M, Steyrn ME, van Rensburg BW, et al. Melatonin in chronic renal failure. Nephron 1992;60:138–142PubMedGoogle Scholar
  34. 34.
    Martin XD, Malina HZ, Brennan MC, et al. The ciliary body the third organ found to synthesize indoleamines in humans. Eur J Ophthalmol 1992;2:67–72PubMedGoogle Scholar
  35. 35.
    Cagnacci A. Melatonin in relation to physiology in adult humans. J Pineal Res 1996;21:200–213PubMedGoogle Scholar
  36. 36.
    Menendez-Pelaez A, Reiter RJ. Distribution of melatonin in mammalian tissues: the relative importance of nuclear versus cytosolic localization. J Pineal Res 1993;15:59–69PubMedGoogle Scholar
  37. 37.
    Turek FW, Dugovic C, Zee PC. Current understanding of the circadian clock and the clinical implications for neurological disorders. Arch Neurol 2001;58:1781–1787PubMedGoogle Scholar
  38. 38.
    Morin LP, Allen CN. The circadian visual system. Brain Res Rev 2006;51:1–60PubMedGoogle Scholar
  39. 39.
    Saper CB, Lu J, Chou TC, et al. The hypothalamic integrator for circadian rhythms. Trends Neurosci 2005;28:152–157PubMedGoogle Scholar
  40. 40.
    Moore RY. Neural control of the pineal gland. Behav Brain Res 1996;73:125–130PubMedGoogle Scholar
  41. 41.
    Klein DC, Weller JL, Moore RY. Melatonin metabolism: neural regulation of pineal serotonin: acetyl coenzyme A N-acetyl-transferase activity. Proc Natl Acad Sci USA 1971;68:3107–3110PubMedGoogle Scholar
  42. 42.
    Ho AK, Klein DC. Activation of alfa1-adrenoceptors, protein kinase C, or treatment with intracellular free Ca++ elevating agent's increases pineal phospholipase A2 activity: evidence that protein kinase C may participate in Ca++-dependent alpha 1-adrenergic stimulation of pineal phospholipase A2 activity. J Biol Chem 1987;262: 11764–11770PubMedGoogle Scholar
  43. 43.
    Klein DC, Schaad NL, Namboordiri MA, et al. Regulation of pineal serotonin N-acetyltransferase activity. Biochem Soc Trans 1992;20:299–304PubMedGoogle Scholar
  44. 44.
    Cagnacci A, Soldani R, Yen SSC. The effect of light on core body temperature is mediated by MLT in women. J Clin Endocrinol Metab 1993;76:1036–1038PubMedGoogle Scholar
  45. 45.
    Dollins AB, Lynch HJ, Wurtman RJ, et al. Effects of illumination on human nocturnal serum MLT levels and performance. Physiol Behav 1993;53:153–160PubMedGoogle Scholar
  46. 46.
    Petterborg LJ, Kjelamn BF, Thalen BE, et al. Effects of 15 minute light pulse on nocturnal serum MLT levels in human volunteers. J Pineal Res 1991;10:9–13PubMedGoogle Scholar
  47. 47.
    Reiter RJ. Static and extremely low frequency electromagnetic field exposure: reported on the circadian production of melatonin. J Cell Biochem 1993;51: 394–403PubMedGoogle Scholar
  48. 48.
    Shanahan TL, Kronauer RE, Duffy JF, et al. Melatonin rhythm observed throughout a three-cycle bright-light stimulus designed to reset the human circadian pacemaker. J Biol Rhythms 1999;14:237–253PubMedGoogle Scholar
  49. 49.
    Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian response. Neuron 1994;13: 1177–1185PubMedGoogle Scholar
  50. 50.
    Reppert SM, Godson C, Mahle CD, et al. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel 1b melatonin receptor. Proc Natl Acad Sci USA 1995;92:8734–8738PubMedGoogle Scholar
  51. 51.
    Nosjean O, Ferro M, Coge F, et al. Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 2000;275:31311–31317PubMedGoogle Scholar
  52. 52.
    Reppert SM, Weaver DR, Rivkees SA, et al. Putative melatonin receptors in a human biological clock. Science 1988;242:78–81PubMedGoogle Scholar
  53. 53.
    Al-Ghoul WM, Herman MD, Dubocovich, ML. Melatonin receptor subtype expression in human cerebellum. Neuroreport 1988;9:4063–4068Google Scholar
  54. 54.
    Scher J, Wankiewicz E, Brown GM, et al. Melatonin receptor in the human retina: expression and localization. Invest Ophthalmol Vis Sci 2002;43:889–897PubMedGoogle Scholar
  55. 55.
    Lopez-Gonzalez MA, Calvo JR, Ossuna C, et al. Interaction of melatonin with human lymphocytes: evidence for binding sites coupled to potentiation of cyclic AMP stimulated by vasoactive intestinal peptide and activation of cyclic GMP. J Pineal Res 1992;12:97–104PubMedGoogle Scholar
  56. 56.
    Yie SM, Niles LP, Youglai EV. Melatonin receptors on human granulose cell membranes. J Clin Endocrinol Metab 1995;80:1747–1749PubMedGoogle Scholar
  57. 57.
    van Vuuren RJ, Pitout MJ, van Aswegen, et al. Putative melatonin receptor in human spermatozoa. Clin Biochem 1992;25:125–127PubMedGoogle Scholar
  58. 58.
    Poon AMS, Mak ASY, Luk HT. Melatonin and 2[125] iodomelatonin binding sites in the human colon. Endocrinol Res 1996;22:77–94Google Scholar
  59. 59.
    Vacas MI, Del Zar MM, Martinuzzo DP, et al. Binding sites for [3 H]-melatonin in human platelets. J Pineal Res 1992;13:60–65PubMedGoogle Scholar
  60. 60.
    Doolen S, Krause DN, Dubocovich ML, et al. Melatonin mediates two distinct responses in vascular smooth muscle. Eur J Pharmacol 1998;345:67–69PubMedGoogle Scholar
  61. 61.
    Brydon L, Roka F, Petit L, et al. Dual signalling of human Mel1a a melatonin receptors via G(i2), G(i3), and G(q/11) proteins. Mol Endocrinol 1999;13:2025–2038PubMedGoogle Scholar
  62. 62.
    Brydon L, Petit L, de Coppet P, et al. Polymorphism and signalling of melatonin receptors. Reprod Nutr Dev 1999;39:315–324PubMedGoogle Scholar
  63. 63.
    Liu C, Weaver DR, Jin X, et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 1997;19:91–102PubMedGoogle Scholar
  64. 64.
    Wu YH, Zhou JN, van Heerikhuize J, et al. Decrease MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer's disease. Neurobiol Aging 2007;28:1239–1247PubMedGoogle Scholar
  65. 65.
    Sugden D, Yeh LK, The MT. Design of subtype selective melatonin receptor agonist. Reprod Nutr Dev 1999;39: 335–344PubMedGoogle Scholar
  66. 66.
    Duvocovich ML, Masana MI, Jacob S, et al. Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to asses the pharmacological profile of the rabbit retina ML1 presyn-aptic heteroreceptor. Naunyn-Schmiedebergs Arch Pharmacol 1997;355:365–375Google Scholar
  67. 67.
    Duvocovich ML, Yun K, Al-Ghoul WM, et al. Selective MT2 melatonin receptor antagonist bock melatonin-mediated phase advances in circadian rhythms. FASEB J 1998;12:1211–1220Google Scholar
  68. 68.
    Lotufo CM, Lopes C, Duvocovich ML, et al. Melatonin and N-acetylserotonin inhibits leucocytes rolling and adhesion to rat microcirculation. Eur J Pharmacol 2001;430:351–457PubMedGoogle Scholar
  69. 69.
    McKenzy RS, Melan MA, Passey DK, et al. Dual coupling of MT(1) and MT(2) melatonin receptors to cyclic AMP and phosphoinositide signal transduction cascade their regulation following melatonin exposure. Biochem Pharmacol 2002;63:587–595Google Scholar
  70. 70.
    Nosjean O, Nocolas JP, Klupsch F, et al. Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Biochem Pharmacol 2001;61:1369–1379PubMedGoogle Scholar
  71. 71.
    Eison AS, Mullins UL. Melatonin binding sites are functionally coupled to phosphoinositide hydrolysis in Syrian hamsters RPMI 1846 melanoma cells. Life Sci 1993;53:PL393–PL398PubMedGoogle Scholar
  72. 72.
    Fjaerly O, Lund T, Osterud B. The effect of melatonin on cellular activation processes in human blood. J Pineal Res 1999;26:50–55Google Scholar
  73. 73.
    Benitez-King G, Anton-Tay F. Calmodulin mediates melatonin cytoskeletal effects. Experientia 1993;49: 635–641PubMedGoogle Scholar
  74. 74.
    Becker-Andre M, Wiesenberg I, Schaeren-Wiemers N, et al. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem 1994;269:28531–2834PubMedGoogle Scholar
  75. 75.
    Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep Med 2006;7:17–24PubMedGoogle Scholar
  76. 76.
    Yous S, Andrieux J, Howell HE, et al. Novel naphthalenic ligands with high affinity for the melatonin receptor. J Med Chem 1992;35:1484–1486PubMedGoogle Scholar
  77. 77.
    Loo H, Hale A, D'Haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol 2002;17:239–247PubMedGoogle Scholar
  78. 78.
    Doghramji K. Melatonin and its receptors: a new class of sleep-promoting agents. J Clin Sleep Med 2007;3(5 Suppl):S17–S23PubMedGoogle Scholar
  79. 79.
    Maestroni GJM, Conti A, Pierpaoli W. Role of the pineal gland in immunity: circadian synthesis and release of melatonin modulates the antibody response and antagonize the immunosuppressive effect of corticosterone. J Neuroimmunol 1986;13:19–30PubMedGoogle Scholar
  80. 80.
    Caroleo MC, Frasce D, Nistico G, et al. Melatonin as immunomodulator in immunodeficient mice. Immunopharmacology 1992;2:81–89Google Scholar
  81. 81.
    Steinhilber D, Brungs M, Werz O, et al. The nuclear receptor for melatonin represses 5-lypoxigenase gene expression in human B lymphocytes. J Biol Chem 1995;270: 7037–7040PubMedGoogle Scholar
  82. 82.
    Garcia-Mauriño S, Gonzalez-Haba MG, Calvo JR, et al. Involvement of nuclear binding sites for melatonin in the regulation of IL-2 and IL-6 production by human blood mononuclear cells. J Neuroimmunol 1998;92:76–84PubMedGoogle Scholar
  83. 83.
    Giordano M, Palermo MS. Melatonin-induced enhancement of antibody dependent cellular cytotoxicity. J Pineal Res 1991;10:117–121PubMedGoogle Scholar
  84. 84.
    Guerrero JM, Reiter RJ. Melatonin-immune system relationship. Curr Top Med Chem 2002;2:167–179PubMedGoogle Scholar
  85. 85.
    Ianas O, Olnescu R, Badescu I. Melatonin involvement in oxidative stress. Rom J Endocrinol 1991;29:147–153Google Scholar
  86. 86.
    Marshall KA, Reiter RJ, Poeggeler B, et al. Evaluation of the antioxidant activity of melatonin in vitro. Free Radic Biol Med 1996;21:307–315PubMedGoogle Scholar
  87. 87.
    Chan T Y, Tang PL. Characterization of the antioxidant effects of melatonin and related indoleamines in vitro. J Pineal Res 1996;20:187–191PubMedGoogle Scholar
  88. 88.
    Tan DX, Manchester LC, Reiter RJ, et al. A novel melatonin metabolite, cyclic 3-hydroxymelatonin: a biomarker of in vivo hydroxyl radical generation. Biochem Biophys Res Commun 1998;253:614–620PubMedGoogle Scholar
  89. 89.
    Pieri C, Marra M, Moroni F, et al. Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci 1994;55:PL271–PL276PubMedGoogle Scholar
  90. 90.
    Sewerynek E, Reiter RJ, Melchiorri D, et al. Oxidative damage in the liver induced by ischemia-reperfusion: protection by melatonin. Hepatogastroenterology 1996; 43:898–905PubMedGoogle Scholar
  91. 91.
    Blanchard B, Pompon D, Ducrocq C. Nitrosation of melatonin by nitric oxide and peroxynitrite. J Pineal Res 2000;29:184–192PubMedGoogle Scholar
  92. 92.
    Pozo D, Reiter RJ, Calvo JR, et al. Inhibition of cerebellar nitric oxide synthase and cyclic GMP production by melatonin via complex formation with calmodulin. J Cell Biochem 1997;65:430–442PubMedGoogle Scholar
  93. 93.
    Kotler M, Rodríguez C, Sainz RM, et al. Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res 1998;24:83–89PubMedGoogle Scholar
  94. 94.
    Antolin I, Rodriguez C, Sainz RM, et al. Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes. FASEB J 1996;10:882–890PubMedGoogle Scholar
  95. 95.
    Melchiorri D, Reiter RJ, Sewerynek E, et al. Melatonin reduces kainate-induced lipid peroxidation in homogenates of different brain regions. FASEB J 1995;9:1205–1210PubMedGoogle Scholar
  96. 96.
    Poeggeler B, Saarela S, Reiter RJ, et al. Melatonin-a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Ann N Y Acad Sci 1994;738:419–420PubMedGoogle Scholar
  97. 97.
    Hardeland R, Reiter RJ, Poeggeler B, et al. The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. Neurosci Biobehav Rev 1993;17:347–357PubMedGoogle Scholar
  98. 98.
    Dreher F, Gabard B, Schwindt DA, et al. Topical melatonin in combination with vitamins E and C protects skin from ultraviolet-induced erythema: a human study in vivo. Br J Dermatol 1998;139:332–339PubMedGoogle Scholar
  99. 99.
    Vijayalaxmi, Reiter RJ, Leal BZ, et al. Effect of melatonin on mitotic and proliferation indices, and sister chromatid exchange in human blood lymphocytes. Mutat Res 1996;351:187–192PubMedGoogle Scholar
  100. 100.
    Vijayalaxmi, Reiter RJ, Meltz ML, et al. Melatonin: possible mechanisms involved in its ‘radioprotective’ effect. Mutat Res 1998;404:187–189PubMedGoogle Scholar
  101. 101.
    Banerjee S, Margulis L. Mitotic arrest by melatonin. Exp Cell Res 1973;78:314–318PubMedGoogle Scholar
  102. 102.
    Hill SM, Spriggs LL, Simon MA, et al. The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system. Cancer Lett 1992;64:249–256PubMedGoogle Scholar
  103. 103.
    Cos S, Fernández F, Sánchez-Barceló EJ. Melatonin inhibits DNA synthesis in MCF-7 human breast cancer cells in vitro. Life Sci 1996;58:2447–2453PubMedGoogle Scholar
  104. 104.
    Ravindra T, Lakshimi NK, Ahuja YR. Melatonin in the pathogenesis and therapy of cancer. Ind J Med Scim 2006;60:523–535Google Scholar
  105. 105.
    Dawson D, Encel N. Melatonin and sleep in humans. J Pineal Res 1993;15:1–12PubMedGoogle Scholar
  106. 106.
    Kräuchi K, Cajochen C, Wirz-Justice A. A relationship between heat loss and sleepiness: effects of postural change and melatonin administration. J Appl Physiol 1997;83: 134–139PubMedGoogle Scholar
  107. 107.
    Van Den Heuvel CJ, Reid KJ, Dawson D. Effect of atenolol on nocturnal sleep and temperature in young men: reversal by pharmacological doses of melatonin. Physiol Behav 1997;61:795–802Google Scholar
  108. 108.
    Soares JM Jr, Masana MI, Erşahin C, et al. Functional melatonin receptors in rat ovaries at various stages of the oestrous cycle. J Pharmacol Exp Ther 2003;306:694–702PubMedGoogle Scholar
  109. 109.
    Sanchez JJ, Abreu P, Gonzalez-Hernandez T, et al. Estrogens modulation of adrenoceptor responsiveness in the female rat pineal gland: differential expression of intracellular estrogen receptors. J Pineal Res 2004;37:26–35PubMedGoogle Scholar
  110. 110.
    Vanecek J, Klein DC. Melatonin inhibits gonadotropin-re-leasing hormone-induced elevation of intracellular Ca2 + in neonatal rat pituitary cells. Endocrinology 1992;130: 701–707PubMedGoogle Scholar
  111. 111.
    Zemková H, Vaněcek J. Inhibitory effect of melatonin on gonadotropin-releasing hormone-induced Ca2 + oscillations in pituitary cells of newborn rats. Neuroendocrinology 1997;65:276–283PubMedGoogle Scholar
  112. 112.
    Berga SL, Mortola JF, Yen SS. Amplification of nocturnal melatonin secretion in women with functional hypotha-lamic amenorrhea. J Clin Endocrinol Metab 1988;66: 242–244PubMedGoogle Scholar
  113. 113.
    Lockley SW, Skene DJ, Tabandeh H, et al. Relationship between napping and melatonin in the blind. J Biol Rhythms 1997;12:16–25PubMedGoogle Scholar
  114. 114.
    Palm L, Blennow G, Wetterberg L. Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Dev Med Child Neurol 1997;39:319–325PubMedGoogle Scholar
  115. 115.
    Cardinali DP, Brusco LI, Lloret SP, et al. Melatonin in sleep disorders and jet-lag. Neuro Endocrinol Lett 2002;23(1 Suppl):9–13PubMedGoogle Scholar
  116. 116.
    Oxenkrug GF, Requintina PJ. Melatonin and jet lag syndrome: experimental model and clinical implications. CNS Spectr 2003;8:139–148PubMedGoogle Scholar
  117. 117.
    Suhner A, Schlagenhauf P, Johnson R, et al. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int 1998;15:655–666PubMedGoogle Scholar
  118. 118.
    Sack RL, Blood ML, Lewy AJ. Melatonin rhythms in night shift workers. Sleep 1992;15:434–441PubMedGoogle Scholar
  119. 119.
    Roden M, Koller M, Pirich K, et al. The circadian melatonin and cortisol secretion pattern in permanent night shift workers. Am J Physiol 1993;265(1 Pt 2):R261–R267PubMedGoogle Scholar
  120. 120.
    Quera-Salva MA, Guilleminault C, Claustrat B, et al. Rapid shift in peak melatonin secretion associated with improved performance in short shift work schedule. Sleep 1997;20:1145–1150PubMedGoogle Scholar
  121. 121.
    Cavallo A, Ris MD, Succop P, et al. Melatonin treatment of pediatric residents for adaptation to night shift work. Ambul Pediatr 2005;5:172–177PubMedGoogle Scholar
  122. 122.
    Kayumov L, Brown G, Jindal R, et al. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med 2001;63:40–48PubMedGoogle Scholar
  123. 123.
    Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep 2007;30:1445–1459PubMedGoogle Scholar
  124. 124.
    Jan JE, Tai J, Hahn G, et al. Melatonin replacement therapy in a child with a pineal tumor. J Child Neurol 2001;16: 139–140PubMedGoogle Scholar
  125. 125.
    Veerman DP, Imholz BP, Wieling W, et al. Circadian profile of systemic hemodynamics. Hypertension 1995;26: 55–59PubMedGoogle Scholar
  126. 126.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia M, et al. Decreased nocturnal melatonin levels during acute myocardial infarction. J Pineal Res 2002;33:248–252PubMedGoogle Scholar
  127. 127.
    Sewerynek E. Melatonin and the cardiovascular system. Neuroendocrinol Lett 2002;23:79–83PubMedGoogle Scholar
  128. 128.
    Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes: part II: acute-phase reactants and biomarkers of endothelial cell activation. Circulation 2006;113:152–155Google Scholar
  129. 129.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia M, et al. Light/dark patterns of interleukin-6 in relation to the pineal hormone melatonin in patients with acute myocar-dial infarction. Cytokine 2004;26:89–93PubMedGoogle Scholar
  130. 130.
    Dominguez-Rodriguez A, Garcia-Gonzalez M, Abreu-Gonzalez P, et al. Relation of nocturnal melatonin levels to C-reactive protein concentration in patients with ST-segment elevation myocardial infarction. Am J Cardiol 2006;97:10–12PubMedGoogle Scholar
  131. 131.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, et al. Relation of nocturnal melatonin levels to serum matrix metalloproteinase-9 concentrations in patients with myocardial infarction. Thromb Res 2007;120:361–366PubMedGoogle Scholar
  132. 132.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, et al. Light/dark patterns of soluble vascular cell adhesion molecule-1 in relation to melatonin in patients with ST-segment elevation myocardial infarction. J Pineal Res 2008;44:65–69PubMedGoogle Scholar
  133. 133.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez M, et al. Prognostic value of nocturnal melatonin levels as a novel marker in patients with ST-segment elevation myocardial infarction. Am J Cardiol 2006;97: 1162–1164PubMedGoogle Scholar
  134. 134.
    Stone BM, Turner C, Mills SL, et al. Hypnotic activity of melatonin. Sleep. 2000;23:663–669PubMedGoogle Scholar
  135. 135.
    Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 2005;20: 1151–1158PubMedGoogle Scholar
  136. 136.
    Suresh Kumar PN, Andrade C, Bhakta SG, et al. Melatonin in schizophrenic outpatients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2007;68: 237–241Google Scholar
  137. 137.
    Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry. 1998;155:1119–1121PubMedGoogle Scholar
  138. 138.
    McIsaac WM. A biochemical concept of mental disease. Postgrad Med 1961;30:111–118PubMedGoogle Scholar
  139. 139.
    Altschule MD. Some effects of aqueous extracts of acetone-dried beef-pineal substance in chronic schizophrenia. N Engl J Med 1957;257:919–922PubMedGoogle Scholar
  140. 140.
    Eldred SH, Bell NW, Sherman LJ. A pilot study comparing the effects of pineal extract and a placebo in patients with chronic schizophrenia. N Engl J Med 1960;263: 1330–1335PubMedGoogle Scholar
  141. 141.
    Wurtman RJ, Axelrod J. Effect of chlorpromazine and other drugs on the disposition of circulating melatonin. Nature 1966;212:312PubMedGoogle Scholar
  142. 142.
    Kunz D, Schmitz S, Mahlberg R, et al. A new concept for melatonin deficit: on pineal calcification and melatonin excretion. Neuropsychopharmacology 1999;21:765–772PubMedGoogle Scholar
  143. 143.
    Sandyk R, Kay SR. Pineal calcification and its relationship to hallucinations in schizophrenia. Int J Neurosci 1992;64: 217–219PubMedGoogle Scholar
  144. 144.
    Hartley R, Smith JA. Formation in vitro of N-acetyl-3,4-dimethoxyphenethylamine by pineal hydroxyl-indole-O-methyl transferase. Biochem Pharmacol 1973;22: 2425–2428PubMedGoogle Scholar
  145. 145.
    Hempel K, Ullrich H, Philippu G. Quantitative investigation on the urinary excretion and metabolism of 3,4-dimethoxyphenylethylamine in schizophrenics and normal individuals. Biol Psychiatry 1982;17:49–59PubMedGoogle Scholar
  146. 146.
    Smith JA, Mee TJ, Padwick DJ, et al. Human post-mortem pineal enzyme activity. Clin Endocrinol (Oxf) 1981;14: 75–81Google Scholar
  147. 147.
    Garelis E, Gillin JC, Wyatt RJ, et al. Elevated blood serotonin concentrations in unmediated chronic schizophrenic patients: a preliminary study. Am J Psychiatry 1975;132: 184–186PubMedGoogle Scholar
  148. 148.
    DeLisi LE, Neckers LM, Weinberger DR, et al. Increased whole blood serotonin concentrations in chronic schizophrenic patients. Arch Gen Psychiatry 1981;38:647–650Google Scholar
  149. 149.
    Crow TJ. Molecular pathology of schizophrenia: more than one disease process? Br Med J 1980;280:66–68PubMedGoogle Scholar
  150. 150.
    Sandyk R, Kay SR. Pineal melatonin in schizophrenia: a review and hypothesis. Schizophr Bull 1990;16: 653–662PubMedGoogle Scholar
  151. 151.
    Tan DX, Manchester LC, Reiter RJ, et al. Cyclic 3-hydroxymelatonin: a melatonin metabolite generated as a result of hydroxyl radical scavenging. Biol Signals Recept 1999;8:70–74PubMedGoogle Scholar
  152. 152.
    Antolin I, Rodriguez C, Sainz RM, et al. Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes. FASEB J 1996;10:882–890PubMedGoogle Scholar
  153. 153.
    Gama CS, Salvador M, Andreazza AC, et al. Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in schizophrenia: a study of patients treated with haloperidol or clozapine. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:512–515PubMedGoogle Scholar
  154. 154.
    Zhang XY, Tan YL, Cao LY, et al. Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophr Res 2006;81:291–300PubMedGoogle Scholar
  155. 155.
    Morera AL, Henry M, García-Hernández A, et al. Acute phase proteins as biological markers of negative psychopa-thology in paranoid schizophrenia. Actas Esp Psiquiatr 2007;35:249–252PubMedGoogle Scholar
  156. 156.
    Dietrich-Muszalska A, Olas B, Rabe-Jablonska J. Oxidative stress in blood platelets from schizophrenic patients. Platelets 2005;16:386–391PubMedGoogle Scholar
  157. 157.
    Yao JK, Leonard S, Reddy R. Altered glutathione redox state in schizophrenia. Dis Markers 2006;22:83–93PubMedGoogle Scholar
  158. 158.
    Altschule MD, Siegel EP, Goncz RM, et al. Effect of pineal extracts on blood glutathione level in psychotic patients. AMA Arch Neurol Psychiatry 1954;71:615–618PubMedGoogle Scholar
  159. 159.
    Alstchule MD, Siegel EP, Henneman DH. Blood glutathi-one level in mental disease before and after treatment. AMA Arch Neurol Psychiatry 1952;67:64–68Google Scholar
  160. 160.
    Hartley R, Smith JA. Inhibition of catecholamine oxidation by indoles. Biochem Pharmacol 1972;21:2007–2012PubMedGoogle Scholar
  161. 161.
    Zisapel N. Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting. Cell Mol Neurobiol 2001;21:605–616PubMedGoogle Scholar
  162. 162.
    Laruelle M, Abi-Dargham A, Gil R, et al. Increased dop-amine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999;46:56–72PubMedGoogle Scholar
  163. 163.
    Lerner AB, Case JD, Takahashi Y, et al. Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc 1958;80:2587Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Armando L. Morera
    • 1
  • Pedro Abreu-Gonzalez
    • 2
  • Manuel Henry
    • 1
  1. 1.Department of Internal Medicine, Dermatology and Psychiatry, School of MedicineUniversity of La Laguna, La Laguna, Santa Cruz de TenerifeCanary IslandsSpain
  2. 2.Department of Physiology, School of MedicineUniversity of La Laguna, La Laguna, Santa Cruz de TenerifeCanary IslandsSpain

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