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The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: A preliminary study
BIOL PSYCHIATRY 1991;30:37!-376
37 !
The Effects of Exogenous Meiatonin on the Total Sleep Time and Daytime Alertness of Chronic Insomniacs: A Preliminary Study James G. MacFarlane, John M. Cleghorn, Gregory M. Brown, and David L. Streiner
The effects of exogenous, supraphysiologic doses of melatonin on the total sleep time and daytime alertness of patients with chronic insomnia was examined in a double blind, °ingle crossover study. Melatonin (75 mg per os) or identical placebo was administered at 10 PM daily to 13 insomniac patients for 14 consecutive days. A significant increase in the subjective assessment of total sleep time and daytime alertness was demonstrated with melatonin but not with placebo. However, 7 of the 13 patients reporzed that the active treatment had no sign~cant effect ~.~zsubjective feeling~ of well-being.
introduction This study aimed to determine the effectiveness of consecutive single evening oral doses of melatonin in the initiation and maintenance of sleep in patients with chronic insomi~ia. Melatonin has hypnotic properties in cats after direct hypothalamic administration (Marczynski et al 1964), and in humans after systemic administration (Anton-Tay et al 1971; Barchas et al 1967; Cramer et al 1974). Romijn (1978) went so far as to suggest that the pineal is a "tranquillizing organ," in day-active animals. Changes in pineal function accompany development and aging. At p~,~berty, there is a subst,~'atial reduction in sleep quality with a consequential increase in sleep requirement (Dement and Carskadon 1982), which is paralleled by a reduction in nocturnal melatonin production (Weissenbacher et al 1984). Also, a decline in melatonin production with advancing age (Iguchi et al 1982) is paralleled by a deterioration of normal sleeping patterns (Zepelin 1983). However, pinealectomy does not affect sleeping patterns in rats (Quay 1968) or humans (MacFarlane et al 1984), indicating that the hypnotic properties of melatonin occur only at supraphysiologic levels. Plasma levels as high as 850 pg/ml (5~ 6 times normal physiologic peaks) have been demonstrated after 2.5 mg oral doses (Matthews et al 1981). Doses ranging from 1.7 mg intranasal (Vollrath et al 1981) to 300 mg oral (Lieberman 1986) have been shown to have significant soporific effects in humans. Melatonin could be directly involved with the circadian timing of sleep (Wurtman and
Faculty of Health Sciences. McMaster Uaivetsity. Address reprin~ #eqccst.~to Di. L G. MacFatlane, Sleep Disorders Clinic. The Toronto Hospital, 399 Bathurst St., Toronto, Ontario. MST-2SS. Canada. Received January 22, 1990; revised February 23, 199! © 1991 Society of Biological Psychiatry
0006-3223/911503,50
372
BIOLPSYCHIATRY
J.G. MacFarlane et al
1991;30:371-376
Lieberman 1985). A 2 mg oral dose at 5 PM in humans hastened evening sleepiness, although it took several days for the effect to emerge (Arendt et al !986). Another preliminary study showed that a 5 mg oral dose of melatonin taken at 6 PM (local time) for 14 consecutive days reduced jet-lag symptoms in eight out of eight subjects (Arendt et al 1986). There has been only one report examining the possible .therapeutic benefits of melatonin for the treatment of insomnia (James et al 1990). Acute 1 and 5 mg doses administered to chronic insomniacs showed no changes in either the duration or onset of sleep, while the subjective', perception of overall sleep quality was significantly improved. The compound is well tolerated, and its bioavailability appears unrestricted (Wetterberg 1979). Supraph3siologic ,levels are rapidly obtained with a 2.5 mg oral dose, and are sustained above normal values for several hours (Matthews et al 1981). Therefore, a controlled clinical trial of melatonin versus placebo was ca~ied out in a group of wellcharac.'erized chronic insomniacs.
Methods Thirteen chronic insomniac patients (8 roen, 5 women) aged 25-65 years took part in this study. All were otherwise healthy and had been free of °" . . . . . . . . . ;. . . . . a . . . . :^.~ for at least four weeks. Prior to inclusion patients were interviewed for medical and psychiatric histories and screened for specific ~,eep disorders (e.g., nocturnal myoclonus, sleep apnea, etc.) by polysomnogram. The final diagnosis of chronic insomnia was based, in addition, on subjective ratings of sleep aL'd daytime alertness (sleep diaries and line analogue scales) for one week. This provided data on: (1) sleep onset time, (2) number of awakenings, (3) time of sleep termination, (4) total sleep time, and (5) ir0pairment of daytime functioning. This patient sample reported a history of chronic insomnia ranging from 5 to 38 years duration, in the absence of medical or psychiatric histories. Polysomnographic data revealed a high correlation between subjective and objective measures of sleep (p < 0.01), which ruled out the possibility of sleep-state misperception. Presenting symptoms varied, with five patients reporting sleep-onset insomnia, while the other eight reported varying degrees of difficulty with sleep maintenance. All patients reported profound impairment of daytime functioni~g secondary to a dramatic reduction in total sleep time, which averaged 3.82 hr less than sleep observed in normal controls (MacFarlane et al 1984). Previous trials with normal subjects have explo~ed a range of doses from 2.5 mg (Matthews et al 1981) to 300 mg oral doses (Lieberman 1986), which had significant soporific effects. Therefore, a single-blind preliminary trial was carried out in which two patients with chronic insomnia were given varying doses of melatonin (Sigma, St. Louis) as follows: A = 2.5 mg (week 1); B = 10 mg (week 3); C = 25 mg (week 5); D = 50 nag (week 7); E = 75 mg (week 9); F = 100 mg (week l l).
Effects of Exogenous Melatonin
B1OLPSYCHIATRY
373
1991 ; 3 0 : 3 7 1 - 3 7 6
60,000
(75 rag)
!
50,000 40,0C0 30'000 I 20,000 n
2700 /
Figure 1. Serum melatonin level after a single 2.5 or 75 mg oral dose in two control subjects.
(2.5 rag)
2100 1500 900 300 10 9
I
I
12
15
I
1
E
I
1
18 21 0 3 TIME (Clock Hours)
1
6
9
The patients were to take "A" for seven consecutive days, nothing for the next seven days, tb..n "B" for seven days, etc. They were asked to maintain sleep diaries and alertness assessment scales, and to log any benefits or side effects of the treatment for the entire period. Both patients reported a subjective benefit at a dose of 75 mg and no benefit at 2.5, 10, or 50 mg. Both patients also reported "hangover" effects including an early morning "pressor" headache with the 100 mg dose. Therefore, a dose of 75 mg was chosen for the treatment trial. Plasma levels of melatonin were determined in two control subjects after taking a single 2.5 mg or a single 75 mg oral dose of melatonin at 10 PM (Figure 1), by radioimmunoassay (CIDtech Research Inc., Hamilton, Ontario). A subsequent double-blind, single-crossover, placebo-controlled protocol was performed in which patients took the capsules from bottle "1" during week one, no~hing during week two (washout) and capsules from bottle "2" during week three. Sii~g~e capsules were taken orally each night at 10 PM. One of the bottles contained se"en 75 mg capsules of melatonin and one contained seven lactose capsules only. Six patients started with melatonin, while the other seven started with placebo.
Results Melatonin appeared to be rapidly absorbed at either oral dose, with peak levels occurring within 90 min (Figure 1). The peak value after 2.5 mg dose was 2630 pg/ml. After a 75 mg dose, plasma levels reached 64,730 pg/ml. This is in clear excess of the normal physiologic concentration, which in this patient population ranged between 60-80 pg/ ml. After the 2.5 mg dose, plasma melatonin levels returned to physiologic values within seven hr. After 75 mg, the plasma level was still at 298 pg/ml when the sampling was terminated at 9 AM.
374
t3IOLPSYCHIATRY
J.G.
MacFarlane et al
1991;30:371-376
Melatonin Trial Three important variables were assessed by the i~,Jividual patients during this trial. These were: (1) subjective awareness of melatonin versus placebo, (2) subjective sleep time, and (3) subjective daytime alertness. Because the sleep time was assumed to directly affect daytime alertness in these patients, these were considered dependent variables and therefore multivariate analysis of variance (MANOVA) was performed. There were a total of !82 observations (days) in Lh'-'_strial (91 on melatonin, 91 on placebo). Patients were able to ascertain when they were taking the active compound only 65.9% of the time. This would suggest that there were no obvious side effects that would allow patients to easily identify the melatonin. A MANOVA was applied to all the data with one grouping factor (melatonin or placebo) and for two dependent variables (length of time asleep and daytime alertness). A significant main effect of treatment was apparent for sleep (F = 2.93, df = 12, p < 0.05) and alertness (F = 3.12, df = 12, p < 0.05) (Figure 2). The graphs show that time asleep and alertness covary. It also shows a clear trend of increased time asleep and alertness over the seven days of melatonin administration. However, the Day by Treatment interaction did not reach statistical significance, and there was no significant difference between early and late phase of treatment in the subjective identification of placebo or melatonin. Also, there was no significant order effect.
Discussion A single, 75 mg oral dose of melatonin given on seven consecutive evenings at 10 PM showed a sigr/ficar~t effect on total reported time asleep and daytime alertness in 13 patients with chronic in,;omnia. It is remarkable that most of these patients were experiencing sleep episodes that were substantially longer thar~ any experienced during the baseline week. Stih, 7 of the i3 patients reported that this had no effect on their subjective feeling of well-being, while a MANOVA showed a uniform treatment response by demonstrating a nonsignJficarat Treatment by Subject interaction. The seven subjective nonresponders were able to accurately identff/the active compound only 58.5% of the time-comparable to the other six patients (66.3%). In terms of clinical histories, six of the seven subjective nonresponders reported having met with little or no success after trying a variety of benzodiazepines to tre~t their insomnia. Possibly, these six patients had little optimism as to the outcome. There was also a ~rend for the response to melatonin to be delayed (2 or 3 days), but this did not reach statistical significance (Figure 2). However, the inadequate power of the small sample size in the present study may explain this. This delayed effect has been previously reported (Arendt et al 1984). It is unclear as to the distinction between the sleep-inducing verses the sleep-timing effects of melatonin. Clearly, the acute soporific effects of supraphysiologic doses of melatonin is a demonstration of sleep induction rather that sleep timing. However, both effects may be playing a lo~e in the present study. Improved sleep is in evidence from the first treatment night, but an increased efficacy is observed with repeated treatments. This is not a general principle of benzodia:,~epine treatment. Perhaps an extended treatment interval would demonstrate a clearer treatment response than the present study; coordinating the timing and induction of sleep should create more physiologic harmony than either does on its own.
Effects of Exogenous Melatonin
BIOL PSYCHIATRY
375
1991;30:371-376
I A
5.0 t
O
--O MELATONtN /
\
I I
\
/
3 0
..0 ,,.0 ~'
\
/ / /
4.5 W
~r
I--
4.0
/
iIII
W .J
3.5
3.0 DAY
5.0
4.5 W ._i
O
4.0
l-
Iv" UJ .-I
\ \
3.5
\
b----O •
3.0
2.5}
---•
O ..... O
, 0
PLACEBO MEL ATONIN
, 1
, 2
, 3
~ 4
, 5
~ 6
, 7
,
DAY
Figure 2. Mean time asleep and daytime alertness rating for all patients during placebo ( x 7 days) and melatonin ( x 7 days) treatment. Alertness scale: 0 = wide awake; eaergetic; 7 = cannot stay awake.
376
13JOLPSYCHIATRY 1991;30:371-376
J.G. MacFarlane et al
Future clir~ical trials with melatonin should involve larger sample sizes, and a detailed drug history that includes retrospective assessment of response to treatments, that is, those who avoid drug intervention, those who have had long-term treatment success with drug intervention, and those who have had many different unsuccessful drug treatments. It will be important to determine if there is a differential response to treatment between such groups. Although there appeared to be no significant difference between the two patient groups (sleep-onset insomnia and sleep-maintenance insomnia) with regard to treatment response, this issue needs to be reexamined. Also, and possibly most important, longer treatment intervals will be necessary to carefully examine whether influencing the induction of sleep and/or the timing of sleep best reflects the mechanism of action of melatonin in the successful treatment of patients with chronic insomnia.
References Anton-Tay F, Diaz J, Femandez-Guardiola G (1971): On the effect of melatonin upon human brains: Its possible therapeutic implications. Life Sci 10:841-850. Arendt J, Borberly A, Franey C, Wright J (1984): The effects of chronic, small doses of melatonin given in the late afternoon on fatigue in man: A preliminary study. Neurosci Lett 45:317-321. Arendt L Aldhous M, Marks V (1986): Alleviation of jet-lag by melatonin: Preliminary results of a controlled double blind trial. Br Med J 292:1170. Barchas J, DaCosta F, Spector S (1967): Acute pharmacology of melatonin. Nature 214:919-920. Cramer H, Rudolph J, Consbruch U, Kendel K (1974): On the effects of melatonin on sleep and behaviour in man. Adv Biochem P~:vchopharmacol ! 1:187-191. Dement W, Carskadon M (1982): Current perspectives on daytime sleepiness: The issues. Sleep 5:s56-s66. lguchi H, Kato K-I, lbagashi H (1982): Age dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Metab 55:27-29. James S, Sack D, Rosenthal N, Mendelson W (1990): Melatonin administration in insomnia. N europsychopharmacology 3:19-23. Lieberman H (1986): Behaviour, sleep and melatonin. J Neural Transm 21:233-241. MacFarlane J, Cleghorn J, Brown G (1984): Melatonin and core temperature rhythm in chronic insomnia. Adv Biosci 53:301-306. Marczynski T, Yamaguchi N, Ling GM, Grodzinska L (1964): Sleep ir~duced by the mlministration of melatonin (5-methoxy-N-acetyltryptamine) to the hypothalamus of unrestrained cats. Experimentia 20:435-437. Matthews C, Kennaway D, Fellengerg A, Phillipou G, Cox L, Seamark R (i981): Melatonin in man. Adv Biosci 29:371-381. Quay W (1968): Individual and lack of pineal effect in the rat's circadian locomotor rhythm. Physiol Behav 3:109-118. Romijn H (1978): The pineal, a tranquillizing organ. Life &li 23:225-227. Vollrath L, Serum P, Gammel G (1981): Sleep induction by intranasal application of melatonin. Adv Biosci 29:327-329. Weissenbacher G, Zeitlhuber U, Waldhauser M, Frisch H, Wurtman R (1984): Fall in nocturnal serum melatonin levels during prepuberty and pubescence. Lancet 1:362-365. Wetterberg L (1979): Clinical importance of n ~latonin. Prog Brain Res 52:539-547. Wurtman R, Lieberman H (1985): Melatonin secretion as a mediator of circadian variations in sleep and sleepiness. J Pineal Res 2:301-303. Zepelin H (1983): Normal age related changes in sleep. In Chase M, Weitzman ED (eds), Sleep Disorders: Basic and Clinical Research, New York: SP and Scientific Books.
37 !
The Effects of Exogenous Meiatonin on the Total Sleep Time and Daytime Alertness of Chronic Insomniacs: A Preliminary Study James G. MacFarlane, John M. Cleghorn, Gregory M. Brown, and David L. Streiner
The effects of exogenous, supraphysiologic doses of melatonin on the total sleep time and daytime alertness of patients with chronic insomnia was examined in a double blind, °ingle crossover study. Melatonin (75 mg per os) or identical placebo was administered at 10 PM daily to 13 insomniac patients for 14 consecutive days. A significant increase in the subjective assessment of total sleep time and daytime alertness was demonstrated with melatonin but not with placebo. However, 7 of the 13 patients reporzed that the active treatment had no sign~cant effect ~.~zsubjective feeling~ of well-being.
introduction This study aimed to determine the effectiveness of consecutive single evening oral doses of melatonin in the initiation and maintenance of sleep in patients with chronic insomi~ia. Melatonin has hypnotic properties in cats after direct hypothalamic administration (Marczynski et al 1964), and in humans after systemic administration (Anton-Tay et al 1971; Barchas et al 1967; Cramer et al 1974). Romijn (1978) went so far as to suggest that the pineal is a "tranquillizing organ," in day-active animals. Changes in pineal function accompany development and aging. At p~,~berty, there is a subst,~'atial reduction in sleep quality with a consequential increase in sleep requirement (Dement and Carskadon 1982), which is paralleled by a reduction in nocturnal melatonin production (Weissenbacher et al 1984). Also, a decline in melatonin production with advancing age (Iguchi et al 1982) is paralleled by a deterioration of normal sleeping patterns (Zepelin 1983). However, pinealectomy does not affect sleeping patterns in rats (Quay 1968) or humans (MacFarlane et al 1984), indicating that the hypnotic properties of melatonin occur only at supraphysiologic levels. Plasma levels as high as 850 pg/ml (5~ 6 times normal physiologic peaks) have been demonstrated after 2.5 mg oral doses (Matthews et al 1981). Doses ranging from 1.7 mg intranasal (Vollrath et al 1981) to 300 mg oral (Lieberman 1986) have been shown to have significant soporific effects in humans. Melatonin could be directly involved with the circadian timing of sleep (Wurtman and
Faculty of Health Sciences. McMaster Uaivetsity. Address reprin~ #eqccst.~to Di. L G. MacFatlane, Sleep Disorders Clinic. The Toronto Hospital, 399 Bathurst St., Toronto, Ontario. MST-2SS. Canada. Received January 22, 1990; revised February 23, 199! © 1991 Society of Biological Psychiatry
0006-3223/911503,50
372
BIOLPSYCHIATRY
J.G. MacFarlane et al
1991;30:371-376
Lieberman 1985). A 2 mg oral dose at 5 PM in humans hastened evening sleepiness, although it took several days for the effect to emerge (Arendt et al !986). Another preliminary study showed that a 5 mg oral dose of melatonin taken at 6 PM (local time) for 14 consecutive days reduced jet-lag symptoms in eight out of eight subjects (Arendt et al 1986). There has been only one report examining the possible .therapeutic benefits of melatonin for the treatment of insomnia (James et al 1990). Acute 1 and 5 mg doses administered to chronic insomniacs showed no changes in either the duration or onset of sleep, while the subjective', perception of overall sleep quality was significantly improved. The compound is well tolerated, and its bioavailability appears unrestricted (Wetterberg 1979). Supraph3siologic ,levels are rapidly obtained with a 2.5 mg oral dose, and are sustained above normal values for several hours (Matthews et al 1981). Therefore, a controlled clinical trial of melatonin versus placebo was ca~ied out in a group of wellcharac.'erized chronic insomniacs.
Methods Thirteen chronic insomniac patients (8 roen, 5 women) aged 25-65 years took part in this study. All were otherwise healthy and had been free of °" . . . . . . . . . ;. . . . . a . . . . :^.~ for at least four weeks. Prior to inclusion patients were interviewed for medical and psychiatric histories and screened for specific ~,eep disorders (e.g., nocturnal myoclonus, sleep apnea, etc.) by polysomnogram. The final diagnosis of chronic insomnia was based, in addition, on subjective ratings of sleep aL'd daytime alertness (sleep diaries and line analogue scales) for one week. This provided data on: (1) sleep onset time, (2) number of awakenings, (3) time of sleep termination, (4) total sleep time, and (5) ir0pairment of daytime functioning. This patient sample reported a history of chronic insomnia ranging from 5 to 38 years duration, in the absence of medical or psychiatric histories. Polysomnographic data revealed a high correlation between subjective and objective measures of sleep (p < 0.01), which ruled out the possibility of sleep-state misperception. Presenting symptoms varied, with five patients reporting sleep-onset insomnia, while the other eight reported varying degrees of difficulty with sleep maintenance. All patients reported profound impairment of daytime functioni~g secondary to a dramatic reduction in total sleep time, which averaged 3.82 hr less than sleep observed in normal controls (MacFarlane et al 1984). Previous trials with normal subjects have explo~ed a range of doses from 2.5 mg (Matthews et al 1981) to 300 mg oral doses (Lieberman 1986), which had significant soporific effects. Therefore, a single-blind preliminary trial was carried out in which two patients with chronic insomnia were given varying doses of melatonin (Sigma, St. Louis) as follows: A = 2.5 mg (week 1); B = 10 mg (week 3); C = 25 mg (week 5); D = 50 nag (week 7); E = 75 mg (week 9); F = 100 mg (week l l).
Effects of Exogenous Melatonin
B1OLPSYCHIATRY
373
1991 ; 3 0 : 3 7 1 - 3 7 6
60,000
(75 rag)
!
50,000 40,0C0 30'000 I 20,000 n
2700 /
Figure 1. Serum melatonin level after a single 2.5 or 75 mg oral dose in two control subjects.
(2.5 rag)
2100 1500 900 300 10 9
I
I
12
15
I
1
E
I
1
18 21 0 3 TIME (Clock Hours)
1
6
9
The patients were to take "A" for seven consecutive days, nothing for the next seven days, tb..n "B" for seven days, etc. They were asked to maintain sleep diaries and alertness assessment scales, and to log any benefits or side effects of the treatment for the entire period. Both patients reported a subjective benefit at a dose of 75 mg and no benefit at 2.5, 10, or 50 mg. Both patients also reported "hangover" effects including an early morning "pressor" headache with the 100 mg dose. Therefore, a dose of 75 mg was chosen for the treatment trial. Plasma levels of melatonin were determined in two control subjects after taking a single 2.5 mg or a single 75 mg oral dose of melatonin at 10 PM (Figure 1), by radioimmunoassay (CIDtech Research Inc., Hamilton, Ontario). A subsequent double-blind, single-crossover, placebo-controlled protocol was performed in which patients took the capsules from bottle "1" during week one, no~hing during week two (washout) and capsules from bottle "2" during week three. Sii~g~e capsules were taken orally each night at 10 PM. One of the bottles contained se"en 75 mg capsules of melatonin and one contained seven lactose capsules only. Six patients started with melatonin, while the other seven started with placebo.
Results Melatonin appeared to be rapidly absorbed at either oral dose, with peak levels occurring within 90 min (Figure 1). The peak value after 2.5 mg dose was 2630 pg/ml. After a 75 mg dose, plasma levels reached 64,730 pg/ml. This is in clear excess of the normal physiologic concentration, which in this patient population ranged between 60-80 pg/ ml. After the 2.5 mg dose, plasma melatonin levels returned to physiologic values within seven hr. After 75 mg, the plasma level was still at 298 pg/ml when the sampling was terminated at 9 AM.
374
t3IOLPSYCHIATRY
J.G.
MacFarlane et al
1991;30:371-376
Melatonin Trial Three important variables were assessed by the i~,Jividual patients during this trial. These were: (1) subjective awareness of melatonin versus placebo, (2) subjective sleep time, and (3) subjective daytime alertness. Because the sleep time was assumed to directly affect daytime alertness in these patients, these were considered dependent variables and therefore multivariate analysis of variance (MANOVA) was performed. There were a total of !82 observations (days) in Lh'-'_strial (91 on melatonin, 91 on placebo). Patients were able to ascertain when they were taking the active compound only 65.9% of the time. This would suggest that there were no obvious side effects that would allow patients to easily identify the melatonin. A MANOVA was applied to all the data with one grouping factor (melatonin or placebo) and for two dependent variables (length of time asleep and daytime alertness). A significant main effect of treatment was apparent for sleep (F = 2.93, df = 12, p < 0.05) and alertness (F = 3.12, df = 12, p < 0.05) (Figure 2). The graphs show that time asleep and alertness covary. It also shows a clear trend of increased time asleep and alertness over the seven days of melatonin administration. However, the Day by Treatment interaction did not reach statistical significance, and there was no significant difference between early and late phase of treatment in the subjective identification of placebo or melatonin. Also, there was no significant order effect.
Discussion A single, 75 mg oral dose of melatonin given on seven consecutive evenings at 10 PM showed a sigr/ficar~t effect on total reported time asleep and daytime alertness in 13 patients with chronic in,;omnia. It is remarkable that most of these patients were experiencing sleep episodes that were substantially longer thar~ any experienced during the baseline week. Stih, 7 of the i3 patients reported that this had no effect on their subjective feeling of well-being, while a MANOVA showed a uniform treatment response by demonstrating a nonsignJficarat Treatment by Subject interaction. The seven subjective nonresponders were able to accurately identff/the active compound only 58.5% of the time-comparable to the other six patients (66.3%). In terms of clinical histories, six of the seven subjective nonresponders reported having met with little or no success after trying a variety of benzodiazepines to tre~t their insomnia. Possibly, these six patients had little optimism as to the outcome. There was also a ~rend for the response to melatonin to be delayed (2 or 3 days), but this did not reach statistical significance (Figure 2). However, the inadequate power of the small sample size in the present study may explain this. This delayed effect has been previously reported (Arendt et al 1984). It is unclear as to the distinction between the sleep-inducing verses the sleep-timing effects of melatonin. Clearly, the acute soporific effects of supraphysiologic doses of melatonin is a demonstration of sleep induction rather that sleep timing. However, both effects may be playing a lo~e in the present study. Improved sleep is in evidence from the first treatment night, but an increased efficacy is observed with repeated treatments. This is not a general principle of benzodia:,~epine treatment. Perhaps an extended treatment interval would demonstrate a clearer treatment response than the present study; coordinating the timing and induction of sleep should create more physiologic harmony than either does on its own.
Effects of Exogenous Melatonin
BIOL PSYCHIATRY
375
1991;30:371-376
I A
5.0 t
O
--O MELATONtN /
\
I I
\
/
3 0
..0 ,,.0 ~'
\
/ / /
4.5 W
~r
I--
4.0
/
iIII
W .J
3.5
3.0 DAY
5.0
4.5 W ._i
O
4.0
l-
Iv" UJ .-I
\ \
3.5
\
b----O •
3.0
2.5}
---•
O ..... O
, 0
PLACEBO MEL ATONIN
, 1
, 2
, 3
~ 4
, 5
~ 6
, 7
,
DAY
Figure 2. Mean time asleep and daytime alertness rating for all patients during placebo ( x 7 days) and melatonin ( x 7 days) treatment. Alertness scale: 0 = wide awake; eaergetic; 7 = cannot stay awake.
376
13JOLPSYCHIATRY 1991;30:371-376
J.G. MacFarlane et al
Future clir~ical trials with melatonin should involve larger sample sizes, and a detailed drug history that includes retrospective assessment of response to treatments, that is, those who avoid drug intervention, those who have had long-term treatment success with drug intervention, and those who have had many different unsuccessful drug treatments. It will be important to determine if there is a differential response to treatment between such groups. Although there appeared to be no significant difference between the two patient groups (sleep-onset insomnia and sleep-maintenance insomnia) with regard to treatment response, this issue needs to be reexamined. Also, and possibly most important, longer treatment intervals will be necessary to carefully examine whether influencing the induction of sleep and/or the timing of sleep best reflects the mechanism of action of melatonin in the successful treatment of patients with chronic insomnia.
References Anton-Tay F, Diaz J, Femandez-Guardiola G (1971): On the effect of melatonin upon human brains: Its possible therapeutic implications. Life Sci 10:841-850. Arendt J, Borberly A, Franey C, Wright J (1984): The effects of chronic, small doses of melatonin given in the late afternoon on fatigue in man: A preliminary study. Neurosci Lett 45:317-321. Arendt L Aldhous M, Marks V (1986): Alleviation of jet-lag by melatonin: Preliminary results of a controlled double blind trial. Br Med J 292:1170. Barchas J, DaCosta F, Spector S (1967): Acute pharmacology of melatonin. Nature 214:919-920. Cramer H, Rudolph J, Consbruch U, Kendel K (1974): On the effects of melatonin on sleep and behaviour in man. Adv Biochem P~:vchopharmacol ! 1:187-191. Dement W, Carskadon M (1982): Current perspectives on daytime sleepiness: The issues. Sleep 5:s56-s66. lguchi H, Kato K-I, lbagashi H (1982): Age dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Metab 55:27-29. James S, Sack D, Rosenthal N, Mendelson W (1990): Melatonin administration in insomnia. N europsychopharmacology 3:19-23. Lieberman H (1986): Behaviour, sleep and melatonin. J Neural Transm 21:233-241. MacFarlane J, Cleghorn J, Brown G (1984): Melatonin and core temperature rhythm in chronic insomnia. Adv Biosci 53:301-306. Marczynski T, Yamaguchi N, Ling GM, Grodzinska L (1964): Sleep ir~duced by the mlministration of melatonin (5-methoxy-N-acetyltryptamine) to the hypothalamus of unrestrained cats. Experimentia 20:435-437. Matthews C, Kennaway D, Fellengerg A, Phillipou G, Cox L, Seamark R (i981): Melatonin in man. Adv Biosci 29:371-381. Quay W (1968): Individual and lack of pineal effect in the rat's circadian locomotor rhythm. Physiol Behav 3:109-118. Romijn H (1978): The pineal, a tranquillizing organ. Life &li 23:225-227. Vollrath L, Serum P, Gammel G (1981): Sleep induction by intranasal application of melatonin. Adv Biosci 29:327-329. Weissenbacher G, Zeitlhuber U, Waldhauser M, Frisch H, Wurtman R (1984): Fall in nocturnal serum melatonin levels during prepuberty and pubescence. Lancet 1:362-365. Wetterberg L (1979): Clinical importance of n ~latonin. Prog Brain Res 52:539-547. Wurtman R, Lieberman H (1985): Melatonin secretion as a mediator of circadian variations in sleep and sleepiness. J Pineal Res 2:301-303. Zepelin H (1983): Normal age related changes in sleep. In Chase M, Weitzman ED (eds), Sleep Disorders: Basic and Clinical Research, New York: SP and Scientific Books.