Nocturnal plasma melatonin concentrations in healthy volunteers: Effect of single doses of d-fenfluramine, paroxetine, and ipsapirone (original) (raw)
Related papers
British Journal of Clinical Pharmacology, 1994
Acute administration of the specific serotonin uptake inhibitor, fluvoxamine (100 mg at 16.00 h), markedly increased nocturnal plasma melatonin concentrations, with high levels extending into the morning hours. 2 Acute administration of the noradrenaline uptake inhibitor, desipramine (DMI) (100 mg at 16.00 h), increased evening plasma melatonin concentrations. 3 Both drug treatments increased the duration of melatonin secretion, fluvoxamine significantly delaying the offset time and DMI significantly advancing the onset time. 4 The stimulatory effect of DMI on plasma melatonin was mirrored by increased urinary 6-sulphatoxymelatonin (aMT6s) excretion. 5 On the contrary, there was no correlation between plasma melatonin and urinary aMT6s concentrations following fluvoxamine treatment, suggesting that fluvoxamine may inhibit the metabolism of melatonin. 6 Treatment with DMI increased plasma cortisol concentrations in the evening and early morning, treatment with fluvoxamine increased plasma cortisol at 03.00 h, 10.00 h and 11.00 h. 7 The drug treatments affected different aspects of the nocturnal plasma melatonin profile suggesting that the amplitude of the melatonin rhythm may depend upon serotonin availability and/or melatonin metabolism whilst the onset of melatonin production depends upon noradrenaline availability.
The circadian pacemaker or biological clock, located in the hypothalamic suprachiasmatic nucleus, is the generation site of circadian rhythms. The light/dark cycle is the circadian pacemaker's dominant synchronizing agent, though it is also influenced by neurotransmitters and the phase-shifting effects of various chemical and pharmacological components, of which melatonin (N-acetyl-5-methoxytryptamine) is the most well established. In recent years, melatonin and melatonin analogs have been commercialized in many countries, mainly with hypnotic purposes. A new compound, agomelatine, has been recently synthesized and studied. Among melatonin analogs, this drug possesses unique pharmacological and clinical features; it is an antagonist at 5-HT2B and 5-HT2C receptors and has well established antidepressant and anxiolytic properties. Agomelatine opens new perspectives in the chronobiotic treatment of depression. The purpose of the present review was to elucidate the effects of the melatonergic system on sleep and the implications for the treatment of psychiatric disorders.
Effects of indirectly acting 5-HT receptor agonists on circulating melatonin levels in rats
1993
Because circulating melatonin levels are generally thought to be under the strict control of pineal N-acetyltransferase, little attention has been paid to the impact of an altered availability of serotonin (5-HT) on melatonin formation. In order to see whether melatonin synthesis is stimulated by an increased availability of free, cytosolic 5-HT, we studied the effects of 5-HT precursors, 5-HT releasers and reuptake inhibitors and of monoamine oxidase inhibitors, alone and in combination, on circulating melatonin levels in experimental animals. The administration of tryptophan and 5-HT-releasing drugs (fenfluramine, + 3,4-methylenedioxymethamphetamine) to rats caused a dose-and time-dependent elevation of circulating melatonin levels during the day and night. This increase in melatonin was further enhanced by inhibition of monoamine oxidase. The elevation of plasma melatonin caused by 5-HT-releasing drugs was prevented by prior administration of fluoxetine. Monoamine oxidase inhibitors and fluoxetine alone had no effect on circulating melatonin levels. These findings indicate that the administration ot indirectly acting 5-HT receptor agonists which increase the free cytoplasmic pool of 5-HT may also elevate circulating melatonin levels. The results of this study suggest that the rate of pineal melatonin synthesis is dependent on the free cytoplasmic pool of 5-HT in pineaiocytes and that the drug-induced elevation of this pool stimulates melatonin formation and increases circulating melatonin levels. At least some of the effects of indirectly acting 5-HT receptor agonists, e.g. on sleep, mood, food intake, pain perception, and neuroendocrine secretion, may therefore be mediated by the elevation of circulating melatonin and the subsequent activation of central melatonin receptors.
Melatonin agonists for treatment of sleep and depressive disorders
Journal of Experimental and Integrative Medicine, 2011
Melatonin the hormone secreted by the pineal gland has been effective in improving sleep both in normal sleepers and insomniacs and has been used successfully in treating sleep and circadian rhythm sleep disorders. The lack of consistency in the reports published by the authors is attributed to the differential bioavailabilty and short half-life of melatonin. Sleep disturbances are also prominent features of depressive disorders. To overcome this problem, melatonergic agonists with sleep promoting properties have been introduced in clinical practice. Ramelteon, the MT1/ MT2 melatonergic agonist, has been used in a large number of clinical trials involving chronic insomniacs and has been found effective in improving the total sleep time and sleep efficiency of insomniacs and has not manifested serious adverse effects. The development of another MT1/MT2 melatonergic agonist agomelatine with antagonsim to 5-HT2c serotonin receptors has been found useful not only in treating sleep problems of patients but also as a first line antidepressant with earlier onset of actions in patients with major depressive disorder. An agonist for MT3 melatonin receptor has also been found effective in animal models of depression.
Differential Effects of Fluvoxamine and Other Antidepressants on the Biotransformation of Melatonin
Journal of Clinical Psychopharmacology, 2001
Melatonin, the predominant product of the pineal gland, is involved in the maintenance of diurnal rhythms. Nocturnal blood concentrations of melatonin have been shown to be enhanced by fluvoxamine, but not by other serotonin reuptake inhibitors. Because fluvoxamine is an inhibitor of several cytochrome P450 (CYP) enzymes, the authors studied the biotransformation of melatonin and the effects of fluvoxamine on the metabolism of melatonin in vitro using human liver microsomes and recombinant human CYP isoenzymes. Melatonin was found to be almost exclusively metabolized by CYP1A2 to 6-hydroxymelatonin and Nacetylserotonin with a minimal contribution of CYP2C19. Both reactions were potently inhibited by fluvoxamine, with a K i of 0.02 M for the formation of 6-hydroxymelatonin and 0.05 M for the formation of N-acetylserotonin. Other than fluvoxamine, fluoxetine, paroxetine, citalopram, imipramine, and desipramine were also tested at 2 and 20 M. Among the other antidepressants, only paroxetine was able to affect the metabolism of melatonin at supratherapeutic concentrations of 20 M, which did not reach by far the magnitude of the inhibitory potency of fluvoxamine. The authors concluded that fluvoxamine is a potent inhibitor of melatonin degradation. Because this inhibitory action is also found in vivo, fluvoxamine might be used as an enhancer of melatonin, which might offer new therapeutic possibilities of fluvoxamine.
Acute treatment with desipramine stimulates melatonin and 6-sulphatoxy melatonin production in man
British Journal of Clinical Pharmacology, 1986
Acute administration of the antidepressant drug desipramine (DMI) in man, increased evening melatonin secretion, which reached peak plasma levels 2-4 h earlier than after placebo administration. 2 The increase at set time points 21.00 h-22.00 h was directly proportional to an individual's integrated night-time secretion of melatonin. 3 We have shown that this stimulation was not an effect of DMI inhibition on the hepatic metabolism of melatonin to 6-sulphatoxy melatonin (aMT6s), indeed aMT6s is in itself a good index of the evening melatonin rise. 4 The stimulation of early evening melatonin by DMI might be exploited as a simple pineal function test.
Melatonin and clinical application
Reproduction Nutrition Development, 1999
A review of the different publications dealing with melatonin in humans shows that this field has been very active in the last few years. Normative melatonin values have been defined. Various relationships between melatonin and other traits have been studied, such as sleep, circadian rhythm, surgical stress and anaesthesia. Age-related melatonin studies and melatonin during depression and other psychiatric disorders have been reviewed. Finally, some studies have been performed to use melatonin as a medication for sleep disturbance in depression, for jet-lag and as a skin protector for ultraviolet light. © Inra/Elsevier, Paris melatonin / clinics / depression / sleep / circadian Résumé ― Mélatonine et applications cliniques. Une revue des différentes publications traitant de la mélatonine chez l'homme montre que ce champ a été très actif au cours de ces dernières années. Des normes de concentrations de mélatonine ont été définies. Diverses relations entre la mélatonine et d'autres caractéristiques comme le sommeil, les rythmes circadiens, le stress chirurgical et l'anesthésie ont été étudiées. Des études sur la mélatonine au cours du vieillissement et sur la mélatonine pendant la dépression et au cours d'autres désordres psychiatriques ont été conduites. Enfin, plusieurs essais ont utilisé la mélatonine comme médicament pour traiter les troubles du sommeil pendant la dépression, pour atténuer le jet-lag et comme protecteur de la peau contre les UV. © Inra/