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Regular Article   |    
The Relation Between the Clinical Subtypes of Delirium and the Urinary Level of 6-SMT
Silviu Balan, M.D.; Arthur Leibovitz, M.D.; Shen Orr Zila, M.Sc.; Mishiev Ruth, M.D.; Wechsler Chana, M.A.; Blumenfeld Yassica, M.A.; Biton Rahel, B.A.; Goldstein Richard, M.D.; Elon Neumann, M.Sc.; Boris Blagman, M.D.; Beni Habot, M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2003;15:363-366. doi:10.1176/appi.neuropsych.15.3.363
View Author and Article Information

Received September 25, 2001; revised February 26, 2002; accepted March 19, 2002. From the Shmuel Harofe Hospital, Geriatric Medical Center, affiliated with the Sackler School of Medicine, Tel-Aviv University; Beer Yacov, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel, Endocrinological Laboratory, Rambam Hospital, Haifa, Israel, Sleep Laboratory, Assaf Harofeh Medical Center, Tzrifin, Israel. Address correspondence to Dr. Silviu Balan, Shmuel Harofeh Hospital, Geriatric Medical Center Beer Yacov No. 2, Israel, code 70300; shmuelh@netvision.net.il (E-mail).

Delirium is a common syndrome among hospitalized elderly patients. In humans, sleep and circadian rhythms are disturbed during delirium, and both are influenced by the hormone melatonin. This prompted us to investigate the relationship of the clinical subtypes of delirium: 1) hyperactive, 2) hypoactive, and 3) mixed, with melatonin, as reflected by a patient's urinary metabolite 6-SMT. Results support our hypothesis that urinary 6-SMT during delirium was higher in hypoactive and lower in hyperactive patients. Because this is the first time a biochemical parameter related to the clinical subtypes of delirium has been reported, further research on the link between melatonin and delirium is necessary.

Abstract Teaser
Figures in this Article

Delirium is common among hospitalized elderly patients, with a prevalence estimated between 15% and 50%.1,2 This syndrome is characterized by disturbances of consciousness, attention, and global changes in cognition. Moreover, abnormalities of mood, perception, and behavior are frequent. All these symptoms fluctuate during the day. The sleep patterns of delirious patients are usually disturbed as well. At times, the entire sleep—wake cycle is reversed: patients are drowsy and nap during the day, whereas night sleep is short and fragmented.3 Melatonin, a hormone with hypnotic effects that increase the propensity to sleep and its duration and quality, is one factor that influences human sleep patterns.4,5,6,7,8 Melatonin also seems to be related to the biological regulation of the circadian rhythms.9,10,11,12,13 Thus, disturbances of sleep and circadian rhythms, as seen in delirious patients, and the known influence of melatonin on these physiological parameters warrant the search for a possible link between the delirium syndrome and melatonin. To date, the only study investigating a possible link between delirium and melatonin is that of Mukai et al.,14 who studied patients with alcohol withdrawal delirium and reported changes in melatonin production during the delirium. Although these changes were specific for the delirium period, their pattern was inconsistent. According to clinical expression, the delirium syndrome can be classified into three subtypes: hyperactive, hypoactive, and mixed.15 Given the known effects of melatonin, we hypothesized that some relation could exist between melatonin blood levels and the subtypes of delirium. A high level of melatonin may be expected in the hypoactive type and a low level in the hyperactive type. The aim of this study was to measure urinary 6-sulphatoxymelatonin (6-SMT) as an indicator of the melatonin level in all three groups of delirious patients and to look for a link between the melatonin level and the clinical subtypes of this syndrome.

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The Patients

This prospective study was performed over a period of 4 months in the three medical wards of the Shmuel Harofe Geriatric Hospital in Israel. The patients were diagnosed according to the International Classification of Diseases (ICD-10) criteria.16 All the patients who developed delirium during hospitalization were included in the study, consecutively. Each patient diagnosed as delirious was also evaluated using a modified form (excluding the temporal onset) of the Delirium Rating Scale (DRS).17 In the first evaluation, the DRS cutoff point for inclusion was a score of 14 points. All the patients were assessed daily, and recovery was considered when a score of less than 6 points was reached. According to their symptoms, the patients were divided into three groups: A = hyperactive patients, B = mixed patients, and C = hypoactive patients.15 The patients' demographic characteristics are summarized in t1.

Excluded from the study were patients who were delirious upon admission and those who had impaired liver or renal function. Proxies of the participants in the study were informed and gave their consent.

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Melatonin Assessment

Melatonin is rapidly metabolized, mainly in the liver, by hydroxylation and after conjugation with sulfuric or glucuronic acid, and it is excreted in the urine. The urinary excretion of 6-sulphatoxymelatonin (6-SMT)—the chief metabolite of melatonin—closely parallels serum melatonin concentrations.18 Therefore, the urinary excretion of 6-SMT can serve as a reliable measurement of serum melatonin.19 We measured 6-SMT urinary levels twice: first in the acute phase of delirium (on the day when DRS showed 14 points) and again after recovery (on the first day when DRS showed 6 points). A 24-hour urine sample was collected from each patient. The urine volume was measured, and 1-ml duplicate samples were frozen. The samples were coded and sent to the endocrinological laboratory of Rambam Hospital for measurement of urinary 6-SMT by radioimmunoassay.20,21 The laboratory team was not told the significance of the samples' codes. Melatonin serum concentration is influenced by different physiological parameters such as age, height, and weight22,23 and by various illnesses, like depression, orthostatic hypotension,24 insomnia,23 cluster headache,25 and bronchial asthma.26 Because of genetics, healthy people also have different melatonin values: some individuals present low values, whereas others have high values.27 Some studies have shown that hospitalization in itself may influence the circadian pattern of melatonin secretion in the elderly population.28,29 Because of the numerous factors that influence melatonin serum concentration, it was almost impossible to find matched controls for the delirious patients we studied. Moreover, the fact that the melatonin levels showed marked intra-individual stability30,31 prompted us to have each patient in the recovery stage represent his own control.

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Statistical Methods

The mean and standard deviation values of 6-SMT for each of the three groups were calculated. For each group, a t test for dependent samples was used for comparison of 6-SMT values under two conditions: acute delirium and after recovery. The MANOVA test for repeated measurements was used to analyze any possible differences in the 6-SMT mean values among the three groups of patients regarding the two measurements.

The study investigated 31 patients: 18 women and 13 men; the mean age was 83.5 ± 7.1 (ranging from 72 to 94 years). Clinically, 7 patients were hyperactive, 10 hypoactive, and 14 mixed. There were no significant differences between the groups regarding mean age, gender, and delirium duration (t1). All the patients suffered from various chronic diseases and were taking between 3 and 7 different drugs (t2). Among the hyperactive patients, the levels of 6-SMT were lower during the acute delirium state than after recovery (p < 0.001). In contrast, among the hypoactive patients, the levels of 6-SMT were higher during the acute delirium state than after recovery (p < 0.01). With the mixed patients, there was no difference in the level of 6-SMT between the two phases of delirium (p < 0.45) (t3). The results of the MANOVA test indicated that a common factor exists between the 6-SMT values in all three groups, in both measurements: F = 58.37 on two degrees of freedom, p < 0.001.

Our data suggest that a relation exists between the delirium syndrome and melatonin. This relation was demonstrated previously in a group of alcohol withdrawal-induced delirium patients.14 This is also suggested by the inverse relationship between the incidence of delirium and the length of the daylight hours, as we have recently reported.32 Moreover, the results support our early hypothesis that patients, when compared at the recovery stage, with delirium of the hyperactive subtype may have lower levels of 6-SMT, whereas those with the hypoactive subtype have higher levels of 6-SMT. No significant differences between the two stages were found in patients with delirium of the mixed type. Hence, the unanswered question is the meaning of these data. Is the clinical expression of the delirium syndrome influenced by the sedative-hypnotic effects of melatonin? Such a relation was previously reported by Wahlund and co-workers, who found that melatonin levels were associated with the level of psychomotor activity in subtypes of affective disorders.33 According to the clinical picture of delirious patients, Liptzin and Levkoff classified the delirium syndrome into subtypes.15 These subtypes differ not only in the symptom profile and severity, but they also may differ in pathophysiologies, responsiveness to therapeutic interventions, and outcome.34 Given the known sedative effect of melatonin, it is tempting to speculate that the clinical expression of the hyperactive or hypoactive types of delirium is related to the amount of its secretion: low levels of melatonin in hyperactive and high levels of melatonin in hypoactive patients. However, the question still arises as to why it is higher in some patients and lower in others. Further studies are needed to elucidate whether there is a connection with either the extrinsic factors that generate delirium or the intrinsic physiological characteristics of each patient. Notably, this study is the first to report a link between the clinical subtypes of delirium and a biochemical parameter (the urinary 6-SMT). The limitation imposed by the small number of patients here suggests the need for further studies before any conclusion can be reached regarding the role of melatonin in delirium.

We wish to thank The Buhlmann Laboratories, Switzerland that supplied the melatonin test kit.

 
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TABLE 1. Patients' demographic characteristics (age and gender) and mean duration of delirium for each subgroup (in days).
   
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TABLE 3. The 6-SMT mean values (ng/ml) during acute delirium and later, after recovery.
Lipowski ZJ: Delirium (acute confusional states). JAMA  1987; 258:1789—1792
[CrossRef] | [PubMed]
 
Casey DA, DeFazio JV: Delirium. Postgraduate Medicine  1996; 100:121—134
[PubMed]
 
Kaplan HI, Sadock BJ: Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 8th edition, Baltimore, Maryland: Williams & Wilkins, 1998; pp 320—322
 
Lerner AB, Case JD: Melatonin. Fed Proc  1960; 19:590—592
 
Vollrath L, Semm P, Gammel G: Sleep induction by intranasal application of melatonin. Adv Biosci  1981; 29:327—329
 
Tzischinsky O, Shlitner A, Lavie P: The association between the nocturnal sleep gate and nocturnal onset of urinary 6—sulfatoxymelatonin. J Biol Rhythms  1993; 8:199—209
[CrossRef] | [PubMed]
 
Lieberman HR, Waldhauser F, Garfield G, et al: Effects of melatonin on human mood and performance. Brain Res  1984; 323:201—207
[CrossRef] | [PubMed]
 
Haimov I, Laudon M, Zisapel N, et al: Sleep disorders and melatonin rhythm in elderly people BMJ  1994; 309:167
 
Lewy AJ, Newsome DA: Different types of melatonin circadian secretory rhythms in some blind subjects. J Clin Endocrinol Metab  1983; 56:1103—1107
[CrossRef] | [PubMed]
 
Arendt J, Aldhous M, Marks V: Alteration of jet lag by melatonin: preliminary results of controlled double blind trial. BMJ  1986; 292:1170
 
Waldhauser F, Vierhapper H, Pirich K: Abnormal circadian melatonin secretion in night-shift workers. N Engl J Med  1986; 315:1614
 
Arendt J: Melatonin. Clin Endocrinol  1988; 29:205—229
[CrossRef]
 
Vignau J, English J, Arendt J, et al: Delayed sleep phase syndrome response to melatonin. Lancet  1991; 337:1121—1124
[CrossRef] | [PubMed]
 
Mukai M, Uchimura N, Hirano T, et al: Circadian rhythms of hormone concentrations in alcohol withdrawal. Psychiat Clin Neurosci  1998; 52:238—240
[CrossRef]
 
Liptzin B, Levkoff SE: An empirical study of delirium subtypes. Br J Psychiat  1992; 161:843—845
[CrossRef]
 
World Health Organization. The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research. Geneva, World Health Organization, 1992
 
Trzepacz PT, Baker RW, Greenhouse J: A symptom rating scale for delirium. Psychiat Res,  1988; 23:89—97
[CrossRef]
 
Lynch HJ, Wurtman RJ, Moskowitz MA, et al: Daily rhythm in human urinary melatonin. Science  1975; 187:169—171
[CrossRef] | [PubMed]
 
Mathews CD, Guerin MV, Wang X: Human plasma melatonin and urinary 6-sulphatoxymelatonin: studies in natural annual photoperiod and in extended darkness. Clin Endocrinol  1991; 35:21—27
[CrossRef]
 
Arendt J, Bojkowski C, Franey C, et al: Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab  1985; 60:1166—1173
[CrossRef] | [PubMed]
 
Aldhous, ME, Arendt J: Radioimmunoassay for 6-sulphatoxymelatonin in urine using an iodinated tracer. Ann Clin Biochemis  1988; 25:298—303
 
Wetterberg L, Bergiannaki JD, Paparrigopoulos T, et al: Normative melatonin excretion: a multinational study. Psychoneuroendocrinology  1999; 24:209—226
[CrossRef] | [PubMed]
 
Blaicher W, Speck E, Imhof MH, et al: Melatonin in postmenopausal females. Arch Gynecol Obstet  2000; 263:116—118
[CrossRef] | [PubMed]
 
Tetsuo M, Polinsky RJ, Markey SP, et al: Urinary 6-hydroxymelatonin excretion in patients with orthostatic hypotension. J Clin Endocrinol Metab  1981; 53:607—610
[CrossRef] | [PubMed]
 
Leone M, Lucini V, D'Amico D, et al: Abnormal 24-hour urinary excretory pattern of 6-sulphatoxymelatonin in both phases of cluster headache. Cephalalgia  1998; 18:664—667
[CrossRef] | [PubMed]
 
Evsyukova HV: The role of melatonin in pathogenesis of aspirin-sensitive asthma. Eur J Clin Invest  1999; 29:563—567
[CrossRef] | [PubMed]
 
Wetterberg L, Bratlid T, et al: A multinational study of the relationships between nighttime urinary melatonin production, age, gender, body size, and latitude. Eur Arch Psychiatry Clin Neurosci  1998; 249:256—262
 
Shilo L, Dagan Y, Smorjik Y, et al: Patients in the intensive care unit suffer from severe lack of sleep associated with loss of normal melatonin secretion pattern. Am J Med Sci  1999; 7:278—281
 
Baskett JJ, Cockrem JF, Todd MA: Melatonin levels in hospitalized elderly patients: a comparison with community based volunteers. Age Ageing  1991; 20:430—434
[CrossRef] | [PubMed]
 
Schulz P, Lustenberger S, Degli Agosti R, et al: Plasma concentration of nine hormones and neurotransmitters during usual activities or constant bed rest. Chronobiol Int  1994; 11:367—380
[CrossRef] | [PubMed]
 
Coetzee JA, Theron JJ, van der Merwe CA: Consecutive melatonin circadian rhythms in normal volunteers. S Afr Med J  1989; 75:163—165
[PubMed]
 
Balan S, Leibovitz A, Freedman L, et al: Seasonal variation in the incidence of delirium among the patients of a geriatric hospital. Archives of Gerontology and Geriatrics (in press)
 
Wahlund B, Grahn H, Saaf J, et al: Affective disorder subtyped by psychomotor symptoms, monoamine oxidase, melatonin and cortrisol: identification of patients with latent bipolar disorder. Eur Arch Psychiatry Clin Neurosci  1998; 248(5):215—224
[CrossRef] | [PubMed]
 
Meagher DJ, O'Hanlon D, O'Mahony E, et al: Relationship between symptoms and motoric subtype of delirium. J Neuropsychiatry Clin Neurosci  2000; 12:1, 51—56
[PubMed]
 
Anchor for JumpAnchor for JumpAnchor for Jump
TABLE 1. Patients' demographic characteristics (age and gender) and mean duration of delirium for each subgroup (in days).
Anchor for JumpAnchor for JumpAnchor for Jump
TABLE 3. The 6-SMT mean values (ng/ml) during acute delirium and later, after recovery.
+

References

Lipowski ZJ: Delirium (acute confusional states). JAMA  1987; 258:1789—1792
[CrossRef] | [PubMed]
 
Casey DA, DeFazio JV: Delirium. Postgraduate Medicine  1996; 100:121—134
[PubMed]
 
Kaplan HI, Sadock BJ: Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 8th edition, Baltimore, Maryland: Williams & Wilkins, 1998; pp 320—322
 
Lerner AB, Case JD: Melatonin. Fed Proc  1960; 19:590—592
 
Vollrath L, Semm P, Gammel G: Sleep induction by intranasal application of melatonin. Adv Biosci  1981; 29:327—329
 
Tzischinsky O, Shlitner A, Lavie P: The association between the nocturnal sleep gate and nocturnal onset of urinary 6—sulfatoxymelatonin. J Biol Rhythms  1993; 8:199—209
[CrossRef] | [PubMed]
 
Lieberman HR, Waldhauser F, Garfield G, et al: Effects of melatonin on human mood and performance. Brain Res  1984; 323:201—207
[CrossRef] | [PubMed]
 
Haimov I, Laudon M, Zisapel N, et al: Sleep disorders and melatonin rhythm in elderly people BMJ  1994; 309:167
 
Lewy AJ, Newsome DA: Different types of melatonin circadian secretory rhythms in some blind subjects. J Clin Endocrinol Metab  1983; 56:1103—1107
[CrossRef] | [PubMed]
 
Arendt J, Aldhous M, Marks V: Alteration of jet lag by melatonin: preliminary results of controlled double blind trial. BMJ  1986; 292:1170
 
Waldhauser F, Vierhapper H, Pirich K: Abnormal circadian melatonin secretion in night-shift workers. N Engl J Med  1986; 315:1614
 
Arendt J: Melatonin. Clin Endocrinol  1988; 29:205—229
[CrossRef]
 
Vignau J, English J, Arendt J, et al: Delayed sleep phase syndrome response to melatonin. Lancet  1991; 337:1121—1124
[CrossRef] | [PubMed]
 
Mukai M, Uchimura N, Hirano T, et al: Circadian rhythms of hormone concentrations in alcohol withdrawal. Psychiat Clin Neurosci  1998; 52:238—240
[CrossRef]
 
Liptzin B, Levkoff SE: An empirical study of delirium subtypes. Br J Psychiat  1992; 161:843—845
[CrossRef]
 
World Health Organization. The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research. Geneva, World Health Organization, 1992
 
Trzepacz PT, Baker RW, Greenhouse J: A symptom rating scale for delirium. Psychiat Res,  1988; 23:89—97
[CrossRef]
 
Lynch HJ, Wurtman RJ, Moskowitz MA, et al: Daily rhythm in human urinary melatonin. Science  1975; 187:169—171
[CrossRef] | [PubMed]
 
Mathews CD, Guerin MV, Wang X: Human plasma melatonin and urinary 6-sulphatoxymelatonin: studies in natural annual photoperiod and in extended darkness. Clin Endocrinol  1991; 35:21—27
[CrossRef]
 
Arendt J, Bojkowski C, Franey C, et al: Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab  1985; 60:1166—1173
[CrossRef] | [PubMed]
 
Aldhous, ME, Arendt J: Radioimmunoassay for 6-sulphatoxymelatonin in urine using an iodinated tracer. Ann Clin Biochemis  1988; 25:298—303
 
Wetterberg L, Bergiannaki JD, Paparrigopoulos T, et al: Normative melatonin excretion: a multinational study. Psychoneuroendocrinology  1999; 24:209—226
[CrossRef] | [PubMed]
 
Blaicher W, Speck E, Imhof MH, et al: Melatonin in postmenopausal females. Arch Gynecol Obstet  2000; 263:116—118
[CrossRef] | [PubMed]
 
Tetsuo M, Polinsky RJ, Markey SP, et al: Urinary 6-hydroxymelatonin excretion in patients with orthostatic hypotension. J Clin Endocrinol Metab  1981; 53:607—610
[CrossRef] | [PubMed]
 
Leone M, Lucini V, D'Amico D, et al: Abnormal 24-hour urinary excretory pattern of 6-sulphatoxymelatonin in both phases of cluster headache. Cephalalgia  1998; 18:664—667
[CrossRef] | [PubMed]
 
Evsyukova HV: The role of melatonin in pathogenesis of aspirin-sensitive asthma. Eur J Clin Invest  1999; 29:563—567
[CrossRef] | [PubMed]
 
Wetterberg L, Bratlid T, et al: A multinational study of the relationships between nighttime urinary melatonin production, age, gender, body size, and latitude. Eur Arch Psychiatry Clin Neurosci  1998; 249:256—262
 
Shilo L, Dagan Y, Smorjik Y, et al: Patients in the intensive care unit suffer from severe lack of sleep associated with loss of normal melatonin secretion pattern. Am J Med Sci  1999; 7:278—281
 
Baskett JJ, Cockrem JF, Todd MA: Melatonin levels in hospitalized elderly patients: a comparison with community based volunteers. Age Ageing  1991; 20:430—434
[CrossRef] | [PubMed]
 
Schulz P, Lustenberger S, Degli Agosti R, et al: Plasma concentration of nine hormones and neurotransmitters during usual activities or constant bed rest. Chronobiol Int  1994; 11:367—380
[CrossRef] | [PubMed]
 
Coetzee JA, Theron JJ, van der Merwe CA: Consecutive melatonin circadian rhythms in normal volunteers. S Afr Med J  1989; 75:163—165
[PubMed]
 
Balan S, Leibovitz A, Freedman L, et al: Seasonal variation in the incidence of delirium among the patients of a geriatric hospital. Archives of Gerontology and Geriatrics (in press)
 
Wahlund B, Grahn H, Saaf J, et al: Affective disorder subtyped by psychomotor symptoms, monoamine oxidase, melatonin and cortrisol: identification of patients with latent bipolar disorder. Eur Arch Psychiatry Clin Neurosci  1998; 248(5):215—224
[CrossRef] | [PubMed]
 
Meagher DJ, O'Hanlon D, O'Mahony E, et al: Relationship between symptoms and motoric subtype of delirium. J Neuropsychiatry Clin Neurosci  2000; 12:1, 51—56
[PubMed]
 
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