Secretion and use of melatonin in circadian rhythm disorders

Melatonin: Clinical perspectives in psychiatric disorders

BIOI.. PSYCHIATRY

225S

1997:42:1$-297$

why SZ Is exacerbated by stress and why neuroleptic drugs can help to alleviate the effect of stress on patients willllllis disorder. Supported by NIMH grants MH00423, MH42261, MH31154 and awards from the Scottish Rite and the Stanley Foundation.

JMemoryoffunctions and schizophrenia: a specific Impairment?

[83-5

pattern

J.-M. Danian, P. Salama. IN5ERM U405, Department of Psychiatry. StrasboUrg. France

It Is now well that memory Impairments are a major aspect of the cognitive diSturbanCeS observed In patients with schizophrenia The magnitude of the memory deficit varies from one patient to another, some of them exhibiting a mar1
In: PsychophalTllllClOlogy, The Fourth

G_ratlon 01 Progress, F.E.

BIOOl11 and O.J. Kupfer (EdltOl'8). New York, Raven Press, pp. 1245-t257.

84. Melatonin: Clinical perspectives in psychiatric disorders

[!4- D Melatonin: From basic science to clinical application L Wetterberg. Department of Clinical Neuroscience. Section of Psychiatry. Karolinska Institute, 5·11281 Stockholm, Sweden The pineal hormone melatonin Is of great Interast for Its circadian regulation of a variety of physiological and neuroendoclme processes and specially regulation of the sleep-wake cycle In health and disease. The synthesis of melatonin and Its production at night Is controlled by a circadian clock within the hypothalamic suprachiasmatlc nucleus and Is synchronized by environmental fight. At the faU of dar1
own production of melatonin. e 9 postoperatively of pinealectomy or some patients on high doses of adrenergic beta-blockers suffers Insomnia and night mares and are often tired In daytime. For such patients sUpplementation with melatonin at night is a proper treatment. It may also be used In delayed-sleep-phase syndrome and as remedy In Jet lag. In some countries melatonin Is sold as a "dietary sUppiemenr, In other It is available only on doctors prescription and In still other countries only In controlled clinical trial. No one yet knows the possible long term risks and side effects of melatonln. A proper dose finding study is also lacking. The use of melatonin as a lay man therapeutic agent has Olrtpaced research on the fundamental physiological and phannaoological actions. The presentation will focus on some of the fundamental aspects of melatonin, Its genetic regulation, seasonal variation, control by light through the human eye and pharmacological aspects with the overall main aim to diagnose low melatonin patients. The production of the pineal hormone melatonin has been shown to be under genetic control (Wettertlerg et aI. 1983). In a further study melatonin has been examined in the night portion of urine In more than 300 apparentiy healthy Individuals for each month of the year under standardized conditions. The statistical analyses show a three component model fitted distribution of the total sample with the mean of urinary melatonin concentration of 0.15, 0.26 and 0.36 nmolesll. Patients with affective disorders, duodenal ulcer, alcoholisms showed melatonin values in the low component with statistically higher frequency. Further genetic analysis combining melatonln concentration with platelet monoamineoxiclase activity and post-dexamethasone suppression test of serum cortisol may be useful In the diagnosis of subgroups of depressed patients taking both the trait and state of the affective disease into considera• tion. The result of new sUbgroups of affective patients with different levels of melatonin will be discussed In light of melatonin as a mar1
order1 using platelet rnon:lSmlne oxidase activity, serum melatonin and post-dexam•

elllasoneeottlaol. Acta PsychiatrScand9131~1 13] Thakln B-E. Merkrld L, I
184-21 secretion and disorders

use of melatonin In circadian rhythm

Josephine Arendt, Debra Skene. University of Surrey, GUJldford, GU25XH, UK The pineal hormone melatonin appears to serve similar functions In all verte~rates. By Its pattem of secretion It conveys information about phase, duratlOA and strength of the daily photoperiod for the organisation of seasonal and circadian physiology. In humans melatonin, suitably timed, will phase shift the endogenous melatonin rtlythm and core body temperature. validated mar1
2268

Melatonin: Clinical perspectives in psychiatric disorders

BIOL. PSYCHIATRY 1997;42:15-2975

the pineal gland Itself and/or Its neural connections, or It could be due to poor perception 01 time cues such as IighVdark as a result of the ageing process and of concomitant changes In behaviour. The reason for low melatonin remains obscure however several attempts to treat sleep disturbance of the elderly have met with success In a small number 01 Individuals. It Is likely that the ability of melatonin to improve sleep, mood and perfor• mance involves both acute effects and circadian phase shift. However when used to entrain sleep in sighted Individuals free running in constant dim light a substantial proportion (25%) of subjects show fragmented sleep pattems during melatonin ingestion compared to placebo. Suitably timed melatonin and bright light are likely to provide optimum conditions for normalising rhythm disturbance. Melatonin may, as a co-ordinator of biological rhythms, help to maintain structured rhythmicity and thereby influence many aspects of health.

184-31 Melatonin, sleep-wake cycle and sleep B. Claustrat, J. Brun, M. Geoffriau, G. Chazot' , M.J. Challamel 2 • Service de Radiopharmacie et Radioanalyse, 1 Service de NeuroJogie C, H6pital NeurrrCarrJiologique, Lyon, 2 Explorations fonctlonnelles neurologiques, centre Hospitalier Lyon-Sud, France The pineal hormone melatonin (MLD Is secreted at night. It Is therefore a natural candidate for the regulation of sleep or sleep-wake cycle in humans. The MLT secretion Is episodic: noctumal plasma MLT show peaks and troughs, if blood Is sampled at close Interval (at least every 20 minutes). Until now, no relationship has been established between peaks or troughs and sleep stages or awakenings, although not completely excluded. Because of a very short plasma MLT half·life, this question should be reevaluated by MLT determination on blood sampled at closer interval (at least every 10 minutes). Experimental phase shifting with bright light or alteration of the photoperiod suggests that the endogenous MLT secretion can Influence sleep architecture or sleep phase duration. Further, in the elderly who show a phase delay and a decrease in the amplitude of the MLT rhythm, sleep responds to MLT replacement which probably acts as a resynchronizer of the circadian sleep-wake cycle and not as a sleeping pill. There is a close relationship between MLT acrophase and temperature through and between MLT and sleep onsets. Data obtained in pathological situations (delayed sleep phase syndrome, advanced sleep phase syndrome, circasemidian rhythm) suggest that a common endogenous clock controls melatonin, temperature and sleep-wake cycles. On the contrary, In sleeping sickness there Is a dissociation between the melatonin secretion which remains located at night and the sleep-wake cycle which Is Iragmented over the 24 h span. MLT Is a chronoblotic: exogenous MLT is able to phase shift the en• dogenous MLT secretion according to a phase response curve, even when given at a physiological dose for a short time. When administered In the late aftemoon or the evening, a phase advance is observed; when MLT is given from the early moming to noon, a phase delay Is observed; the cross-over point is around 3 p.m., opposite the MLT acrophase. On the other hand, MLT displays a soporilic property Q.e. is able to Induce or to facilitate sleep) when given during the day at a high dose, usually several mg per os, leading to supraphysiologlcal plasma MLT levels, several times a noctumal peak. This sleepiness Is documented in specific changes In the waking EEG changes (enhanced theta/alpha activity). The effect on the sleep propensity Is tlme-dependent. This dual property addresses the question 01 whether the endogenous MLT profile should be mimicked using low doses with possibly a sustained release or to use higher pharmacological doses. References [1 J Claustrat B" Brun J., Gany P., Roussel B., Sassolas G.-A once-repeated study of noctumal plasma melatonin pattems and sleep recordings in six normal young men. J. alPlneal Researoh,1986, 3, 301-310.

[2] Deacon S. and Arendt J. Melatonin-Induced temperature suppression and Ita acute phase-shifting effects correlate In a dose-dependenl manner In humans. 8raln Res., 1995,688, n-85. [3J Lewy A.J., 5eeeduddln A., Lelham-Jackson J.M., Sack R.L Melalonin IhIl1a human circadian rhythms according to a phase-response curve. Chronoblol. Int., 1992. 9. 38~92.

(4) zaldan R., Geoflrlau 1.1., Brun J" Talllard J., Bureau C., Chazol G., Claustral B. Mela• tonin Is able to Influence Ita secretion In humans: desc~ption of s phase-response

curve. Neuroendocrlnol., 1994, 60,105-112. (5) W1rz..Juslice A. and Armstrong S.M. Melatonin: nature's soporific? J. Sleep Res., 1996,5,137-141.

184-41 Implications Melatonin and depression: Theoretical and practical A. Wlrz.Justice. Psychiatric University Clinic, CH-4025 Basel, Switzerland Ever since the development 01 the IIrst RIA for melatonin more than twenty years ago, melatonin has been an important focus of research In mood disorders. There are four main reasons why melatonin Is uselul to test hypotheses of the pathophysiology under1ylng affective Illness: first, the syn• thesis of pineal melatonin Is regulated primarily by the sympathetic nervous system, and thus melatonin has been used as a marker for noradrenergic function. Second, since melatonin exhibits a robust circadian rhythm, Its timing and peak can be used to estimate putative phase or amplitude dis• turbances. Third, the effect of acute and chronic antidepressant treatments on melatonin secretion can be compared with clinical response. And fourth, melatonin secretion Is acutely suppressed by light, permitting Its use as a marker 01 light sensitivity in depression. In spite of the clarity of the theory, a review of the literature reveals a somewhat blurry story. Over the years, melatonin rhythms in plasma or excretion of Its metabolite In urine have been studied In patients with major depression. The main finding, not replicated in all studies, Is a blunted n0c• turnal amplitude of melatonin secretion, without any specific phase change. Weight loss per se has no effect on melatonin. Melatonin is not abnormal in anorexia or bulimia nervosa, but low when a concurrent depression Is present. A more specillc chronobiologlcal abnormality has been found In premenstrual depression, 01 an earlier morning offset 01 melatonin secretion, and in some studies 01 winter depressive patients (SAD), of a later dim light melatonin onset (OLMO). Antidepressant drug effects do not lit any pattern that could be linked to clinical response. For example, the noradrenaline uptake Inhibitor desipramine increases melatonin secretion but another, maprotiline, does not. Some serotonin uptake Inhibitors (Imipramine, flu. voxamlne, cltalopram) may also increase melatonin. The MAOls clorgyline or tranylcypromine augment melatonin. whereas the reversible MAOls mo• clobemlde or plr1indole do not. Noteworthy as a methodological waming, is that a single evening dose 01 a benzodlazepine (alprazolam) can blunt the noctumal peak. Sleep deprivation does not affect melatonin (when eamed out under controlled conditions). The question 01 whether manic-depres• slve patients are supersensitive to light (state- or trait-dependent) is still

open.

All these data on melatonin rhythms In depression do not address the corollary question, as to whether melatonin administration, per se, could be antidepressant. In initial studies using extremely high dosage, melatonin ac• tually appeared to be depressogenic. Lower doses (O.1-5 mg) do not affect mood In healthy subjects. Melatonin does not Improve SAD. Melatonin's only effects so lar established are to phase shift the circadian pacemaker (de• pendent on time 01 administration), and Induce sleepiness and hypothermia at any time of day. There are still some important treasures to be mined In a new generation of studies. For non-Invasive, easy sample collection, saliva can replace plasma when extemal conditions are carelully controlled, given the new highly sensitive and selective salivary assays lor OLMO. These can be used for ambulatory long-term studies of Individual patients e.g. circadian phase shifts in mania and depression, winter-summer differences In SAD. Constant routine studies are also important to ensure that the melatonin rhythms measured are not masked by posture, light etc. Finally, further differentiated studies of the effects 01 low-dose melatonin treatment In depression are required belore rejecting lis putative therapeutic potential. The author's studies of melatonin In SAD were funded by the Swiss National Science Foundation.

184-51 Disruption of melatonin circadian rhythm In schizophrenia and obsesslve-compulslve disorder P. Monteleone. M. Natale, A. Fuschlno, M. Maj. Department of Psychiatry, Universily of Naples, Italy

•

Background: Neuroendocrine approaches are now being used extensively in the assessment of neurotransmitter function In psychiatric syndromes in• cluding schizophrenia and obsessive-compulslve disorder (OCO). Howe~e~ In spite of the well-defined circadian rhythmicity of neurohormones the ma: jorlty 01 the neuroendocrine studies, in both schizophrenia and OeD, have used drug-ehallenge paradigms. Relatively few studies have been perfonned on the 24-hour proliles 01 endogenous hormones in these diSOrders Such studies, which give more complete Information on the functional stat~s of a neuroendocrine axis, are mandatory In the case of melatonin, for which no sale drug challenge test is available. We Investigated the circadian pattems