effect of dexfenfluramine on sleep in healthy subjects

Psychopharmacology (1991) 105:213-218 0033315891001973 Psychopharmacology

© Springer-Verlag 1991

Effect of dexfenfluramine on sleep in healthy subjects Michael Wiegand*, Sabine Bossert, Ronald Kinney, Karl-Martin Pirke, and Jiirgen-Christian Krieg

Max Planck Institute of Psychiatry, Kraepelinstrasse 10, W-8000 Mfinchen 40, Federal Republic of Germany

Received November 6, 1990 / Final version March 18, 1991

Abstract. The acute effects of dexfenfluramine on nocturnal sleep were studied in ten healthy male subjects by means of sleep EEG recordings and ratings of subjective sleep quality. Four different dosages (3 mg, 7 rag, 15 mg, and 30 rag) were tested, administered over a period of 3 days each. Under 15 mg and 30 mg dexfenfluramine, only slight effects on sleep were observed: 15 mg led to decreased sleep efficiency in the first night of medication, and to reduced percentage of slow wave sleep in the first and third night. A significant lengthening of REM latency was present in the third night under 30 mg dexfenfluramine, without changes in other REM sleep parameters. Daily doses of 3 mg and 7 mg dexfenfluramine did not influence sleep, except for a significant REM latency reduction observed in the first night under 3 mg. Apart from a transient slight impairment under 30 rag, ratings of subjective sleep quality did not mirror any impact of dexfenfluramine. The data suggest that therapeutic dosages of dexfenfluramine only slightly influence nocturnal sleep, which contrasts with the known impact of other anti-obesity agents like the amphetamines. Un- like classical antidepressants, dexfenfluramine does not reduce REM sleep; in light of a hypothetical link between REM sleep reduction and antidepressant action of a drug, dexfenfluramine is not expected to have a pro- nounced antidepressant effect.

Key words: Dexfenfluramine Serotonin- Sleep EEG

Dexfenfturamine (d-fenfluramine) is the dextrorotatory isomer of dt-fenfluramine. Its mechanism of action is primarily serotoninergic, increasing the release and in- hibiting the reuptake of serotonin. Unlike the racemate,

* Present address: Psychiatric Clinic of the Technical University, Ismaninger Strasse 22, W 8000 Miinchen 80, Federal Republic of Germany

Offprint requests to: M. Wiegand at his present address

dexfenfluramine has no additional direct antidopaminer- gic action. Though similar in molecular structure, its mode of action differs from that of d-amphetamine, which acts specifically upon the catecholaminergic system (Garattini et al. 1987, 1988; Nathan 1987). The elimination half-life of dexfenfluramine is about 18 h (Caccia et al. 1985).

Dexfenfluramine is used primarily in the treatment of obesity: In addition, in patients with seasonal affective disorder (SAD), a mood improving effect has been reported by O'Rourke et al. (1987), with a concomitant de- crease in food intake. This observation appears plausible considering the close relationship between tryptophan/ serotonin regulation, food intake, and mood (Wurtman 1988). In contrast, Hill (1988) failed to find a mood improving effect of dexfenfluramine in patients with premenstrual syndrome. In a study by Russell et al. (1988), dexfenfluramine was found to reduce bulimic symptomatology in outpatients with bulimia nervosa without affecting concomitant depressive symptoms.

A study of the effect of this compound on nocturnal sleep appears useful for several reasons. It is of interest whether dexfenfluramine impairs nocturnal sleep in the same way as other anorectic agents (e.g., the structurally related d-amphetamine; Oswald 1970; Maggini et al. 1988). At present, sufficient sleep-related data are avail- able only for racemic fenfluramine (d/-fenfluramine). Animal experiments have yielded contradictory results: whereas Johnson et al. (1971) found an increase in slow wave sleep and prolonged sleep period time under dl-

fenfluramine in cats, Fornal and Radulovacki (1983a, b) reported decreased slow wave sleep in rats. In man, slight dose-dependent reductions of slow wave sleep, as well as an increase in wakefulness and stage 1, have been reported for patients receiving d/-fenfluramine (Oswald et al. 1968; Gagnon et al. 1969; Lewis 1970; Stunkard et al. 1973). In contrast, chronic administration led to in- creased slow wave sleep (Lewis et al. 1971).

Data regarding the effects of d/-fenfluramine on REM sleep are inconclusive. Oswald et al. (1968) and Lewis

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(1970) did not observe any effect o f an acute medicat ion o f d/-fenfluramine on R E M sleep. However , other studies have revealed a reduct ion in R E M sleep during both acute t reatment ( G a g n o n et al. 1969) and chronic ad- ministrat ion (Lewis et al. 1971). Accord ing to Riley et al. (1966), very high doses (400-800 mg) suppress R E M sleep whereas lower doses p rom o t e an increase in R E M latency only (Fir th et al. 1970). In cats, Johnson et al. (1971) observed R E M sleep suppression, which led to a r ebound after a few days under con t inuous medicat ion. Later, tolerance to the R E M suppressive effect o f fenfluramine occurred. Presumably, the occurrence o f vivid dreams (and even nightmares) in m a n (Alvi 1969; Multen and Wilson 1974; Pinder et al. 1975) is due to rebound phenomena . Forna l and Radu lovack i (1983a, b) reported a dose-dependent suppression o f bo th stow wave sleep and R E M sleep in rats. They hypothesize tha t these effects may result f rom direct act ion o f the drug on postsynapt ic 5 - H T receptors, ra ther than by mediat ing the release o f 5 H T .

The quest ion as to whether R E M sleep is suppressed by dexfenfluramine is o f theoretical relevance with regard to its possible act ion on depressive symptomato logy . Wi th only few exceptions (e.g., t r imipramine, Wiegand and Berger 1989), the major i ty o f efficient ant idepressant drugs reduce the relative a m o u n t o f R E M sleep within a large dose range, while at the same time lengthening R E M latency. This R E M sleep-suppressing effect o f antidepressants is far more p ronounced and lasting than that o f any other psychot ropic drugs (Chen 1979). Since it remains unclear whether R E M sleep suppression is mere- ly an ep iphenomenon o f o r a causal mechanism in antidepressant act ion (McCar ley 1982; Berger et al. 1988), it is o f part icular interest to s tudy the sleep-related effects o f drugs which, like dexfenfluramine, differ structurally f rom classical antidepressants, yet are likely to have antidepressant effects under certain condit ions.

Sleep qual i ty under dexfenfluramine has been investigated by Silverstone et al. (1987), based on healthy subject 's ratings, wi thout po lysomnograph ic verification. Only a fairly high dose (60 mg) o f dexfenfluramine impaired the overall quali ty o f sleep, the ease o f falling off to sleep, and possibly the cont inui ty o f sleep in heal thy subjects, whereas doses o f 30 and 40 mg had no detri- mental effect on sleep.

The present s tudy investigated noc turna l sleep under dosages o f dexfenfluramine, bo th within the therapeutic range applied in the t rea tment o f obesity and under "subtherapeut ic" doses.

Materials and methods

Phases of the study. The study consisted of four phases (I-IV). In each phase, a different daily dosage was administered (I: 15 rag; II: 30 nag; III: 3 mg; IV: 7 mg). Between phases I and II, as well as between phases III and IV, a wash-out period of 10 days was included. Phases II and III were separated by an interval of several months.

Subjects. Ten male subjects between the ages of 18 and 30 (mean age 24.0 ± 3.7 years) volunteered for phases I and II of the study.

Due to the extended interval between phases II and III, four of them could no longer be recruited for phases III and IV and were replaced by four new subjects (mean age 23.4_+ 3.4 years) in phases III and IV. According to a thorough medical and psychiatric examination, all volunteers were free of any acute or chronic illnesses, including drug or alcohol abuse. Their body weight fell within the range of 85 115 % of Ideal Body Weight (IBW, Metropolitan Life Insurance Company 1959). The mean body weight was 69.8 ± 7.5 kg in phases I and II, and 71.3 ±4.5 kg in phases III and IV. All were paid for participation in the study and gave their informed consent. The protocol of the investigation was reviewed by the Advisory Ethics Committee of the Institute. The study was performed according to the declarations of Helsinki and Tokio (World Medical Association 1964, 1975).

Schedule of medication. On day 1 (preceding the first sleep EEG registration) of each phase of the study (I-IV), atl subjects received placebo at 7: 00 and 19: 00 hours. On days 2 through 4, placebo was given at 7:00 hours and verum at 19:00 hours during phases I (15 rag), III (3 rag), and IV (7 mg). tn phase II, 15 nag dexfenfluramine were administered at both 7:00 and 19:00 hours.

Polysomnography. Following an adaptation night in the sleep lab- oratory, nocturnal sleep was recorded polysomnographically after days 1 (baseline), 2 (first night of medication), and 4 (third night of medication) of each phase of the study. The recordings were performed between lights out (23:00 hours) and lights on (7:00 hours) using a 17-channel Nihon Kohden 4417 EEG machine, which measured the following parameters: EEG (C3-A2/C4~A1), EOG (horizontal), and EMG (submental). The sleep polygraphs were rated visually according to standard criteria (Rechtschaffen and Kales 1968). The following definitions of sleep parameters were used:

Sleep period time: time from sleep onset until final awakening. Sleep onset latency: time from lights out until the appearance of stage 2 sleep. Sleep efficiency: ratio of total sleep time to time in bed. REM latency: time from sleep onset until the first occurrence of REM sleep. REM density: number of 3-s "mini-epochs" of REM sleep contain- ing eye movements as a percentage of the total number of "mini- epochs" of REM sleep

Subjects were restricted to non-alcoholic beverages and drinks flee of caffeine during the days immediately preceding sleep recordings. They were instructed to maintain their normal eating behavior, to be as active as usual, and to refrain from taking naps. Before each sleep recording, blood was taken for analysis of plasma levels of dexfenfluramine (and its metabolite d-norfenfluramine) by means of electron capture-gas liquid chromatography.

Self-report measures. Approximately 15 rain before the beginning of each sleep recording, subjects were asked to rate their current mood state and level of fatigue on visual analogue scales t 00 mm in length ("evening questionnaire"). In the morning, mood and fatigue were rated again, together with ratings of subjective sleep parameters, such as subjective sleep quality, sleep onset latency, and experienced sleep continuity ("morning questionnaire"). The ratings on both questionnaires were scored with 0 as the "positive" and 100 as the "negative" pole (=dejected mood, high fatigue, impaired sleep, short sleep duration, and low sleep continuity).

Statistical analysis. The effects of the drug on sleep variables and subjective ratings were tested using Student's t-test for dependent variables (two-tailed). Pearson's correlation coefficients were cal- culated between plasma levels of dexfenfluramine (or d-norfenfluramine) and selected sleep variables. In addition, a multiple regression analysis was performed. The significance level was set at 5%,

Table 1. Sleep during baseline and dexfenfluramine medication (means 4- SD)

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15 mg dexfenfluramine

Baseline 1st night 3rd night Under medication



General sleep variables' Sleep period time (±in) 453.1 ±27.1 440.9±23.9 443.9±23.0 455.2± 19 .8 437.64-36.0 459.74- 14.3 Sleep efficiency (%) 89.9:t: 5.3 85.44- 4.4** 86.6± 5.8 89.9± 7.3 79.84-17.0 88.8± 9.2 Sleep onset latency (±in) 26.44-25.8 34.24- 1 9 . 8 36.0±24.5 24.04- 17.8 40.0:k 31.4 19.4± 12.7 Stage awake (min) 21.24- 1 2 . 9 30.94-24.6 27.84-25.1 23.64-23.5 51.7±52.8 33.44-35.6 Stage 1 (min) 37.3±23.7 43.0±28.7 35.3±27.9 33.14-20.9 36.0±27.4 42.64-32.9 Stage 2 (min) 242.54-26.0 226.34-26.7 253,8±28.0 250.3± 31 .6 226.2±39.4 259.9±38.4 Slow wave sleep (±in) 64.04- 26.6 45.1 4- 24.8** 38.3 ± 25.6** 61.74- 28.3 46.1 ± 29.8 42.8 ± 36.6 Stage awake (% SPT) 4.6± 2.8 6.94- 5.3 6.2+ 5.4 5.34- 5.5 12.7:t:14.3 7.4+ 8.3 Stage 1 (% SPT) 8.1:t: 5.1 9.6± 6.0 7.9± 6.0 7.2:t: 4.5 8.14- 6.1 9.24- 7.1 Stage2(% SPT) 53.64- 5.8 51.54- 7.0 57.54- 8.2 55.0± 6.7 51.54- 6.5 56.54- 7.9 Slow wave sleep (% SPT) 14.04- 5.5 10.34- 5.7** 8.54- 5.5** 13.5+ 6.1 10.3± 6.6 9.34- 7.9

REM sleep variables

REM latency (min) 98.94-38.9 106,94-52.9 126,2±61.3 110.6:t:45.0 141.4±45.9 186.6±68.8"* Stage REM (min) 83.94- 17.7 92.0± 1 3 . 8 85.74-22.3 83.3+28.7 74.34-33.4 77.34-31.3 Stage REM (% SPT) 18.64- 4.3 20.94- 3.3 19.34- 4.9 18.34- 6.1 16.74- 7.1 16.7± 6.4 Duration of 1st REMP (±in) 16.84- 8.9 21.84- 14.2 15.54- 9.8 20.9± 17.9 14.6± 9.9 26.9± 17.8 Density of 1st REMP 20.7± 11.4 23.54- 12.2 18.5± 6.6 22.6± 9.0 16.84- 8.4 23.4± 10.8 REM density (general) 26.6± 8.7 26.6± 7.8 23.6± 6.1 27.6± 8.5 25.3± 7.9 25.5+ 9.7

** P < 0.01 in comparison with baseline

Table 2. Sleep during baseline and dexfenfluramine medication (means ± SD)

3 mg dexfenfturamine



Baseline 1 st night 3rd night Under medication

General sleep variables Sleep period time (min) 442.7123.7 437.9±31.6 442.1± 1 5 . 1 430.8i53.1 434.0± 44.2 427.6±63.1 Sleep efficiency (%) 90.5± 5.2 88.5± 7.2 87.2± 12.1 87.8± 13.2 86.94- I0.6 86.9± 13.1 Sleep onset latency (min) 31.6±21.9 37.7±29.4 31.8± 17.6 27.0± 20.6 40.1 :t:40.9 30.2± 15.5 Stage awake (±in) 12.4± 14.3 t2.7± I2.7 28.4±47.6 14.1 ± 14.6 17.5± 21.2 12.6± 13.7 Stage 1 (min) 22.4±11.7 22,7±11.7 24.14- 8.5 21.8±14.4 27.4±13.0 20.0±13.2 Stage 2 (min) 257.1 ± 17.5 249.5 ± 3 9 . 6 240.54- 42.2 246.0 ± 50.7 240.2 ± 26.2 248.2 ± 35.8 Slow wave sleep (min) 54.4±21.6 54.94-23.0 55.1 4-27.0 61.6±28.3 55.5±24.0 48.5±31.0 Stage awake(% SPT) 2.8± 3.2 3.0± 3.0 6.6±11.2 3.6± 4.1 4.2± 5.4 3.0± 3.1 Stage 1 (% SPT) 5.1± 2.6 5.2± 2.7 5.4± 1.9 5.1± 3.3 6.3± 3.0 4.6± 2.8 Stage 2 (% SPT) 58.2± 5.0 57.0± 7.3 54.3± 8.7 57.04- 8.3 55.6± 5.4 58.6± 7.1 Slow wavesleep (% SPT) 12.2± 4.7 12.4± 4.9 12.5± 6.0 14.4± 6.5 12.6± 5.3 10.8± 6.8

REM sleep variables REM latency (min) 84.0±31.2 71.2±35.5" 102.2±37.3 96.9±43.3 73.3±36.7 86.9±44.6 Stage REM (min) 91.84- 14.2 93.64- 1 7 . 0 90.24-21.1 82.74-27.4 88.5±25.3 91.9±23.5 Stage REM (% SPT) 20.74- 3.6 21.44- 3.5 20.4± 4.6 18.8± 5.2 20.2+ 4.8 21.54- 4.4 Duration of 1st REMP (min) 12.9± 11.6 11.44- 11.4 13.5± 11.4 16.84- 16.7 16.3± 9.3 13.3± 6,3 Density of 1st REMP 21.04- 15.4 17.4± 8.8 20.54- 5.8 18.9± 12.2 19.5± 9.7 18.24- 10.7 REM density (general) 24.54- 9.4 26,1± 8.7 25.04- 9.5 25.5± 11.0 25.0± 11.1 25.3± 10.5

* P< 0.05 in comparison with baseline

Results

Effects on sleep E E G recordings

The effects o f 15 mg and 30 mg dexfenf luramine (phases I and II of the study) on selected sleep parameters are shown in Table 1.

Slow wave sleep unde r 15 mg was significantly reduced dur ing both the 1 st and 3rd n ight ( though nons ig- nif icant unde r 30 mg), and sleep efficiency was lowered in the first n ight o f medicat ion. R E M latency was prolonged unde r bo th 15 mg and 30 mg; however, the dif- ference between basel ine and sleep unde r medica t ion reached statistical significance only for the third n ight

216

Table 3. Plasma levels of dexfenfluramine and its main metabolite (ng/ml; means 4- SD)

Dexfenfluramine d-Norfenfluramine

15 mg 1st night of medication 7.1 ± 4,3 5.0± 3.7 3rd night of medication 11.3 :k 5.4 12.1 ± 2.7

30 mg 1st night of medication 14.7 ± 14.2 10.6 ± 4.5 3rd night of medication 19~1 + 3.1 21.6± 6.0

under 30 mg. There were no significant changes in REM sleep duration or other REM sleep parameters, as well as in all other sleep variables.

Under 3 mg and 7 mg dexfenfluramine (phases III and IV of the study, Table 2), no significant changes in sleep parameters resulted, except for an initial reduction of REM latency in the first night under 3 nag which was no longer present in the third night under medication; under 7 mg, the same tendency prevailed.

Relationship between sleep and plasma levels

Table 3 presents the mean plasma levels of dexfenfluramine and its main metabolite, d-norfenfluramine, during medication in phases I and II. All levels were within the expected range with respect to the dosage administered (Silverstone et al. 1987). Under 3 mg and 7 mg daily dosage (stages III and IV), all plasma concentrations were below the level of quantification.

In phases I fand II, there was no significant correlation between plasma levels and any of the sleep parameters likely to be influenced by dexfenfluramine, except for a significant positive correlation between slow wave sleep and d-norfenfluramine levels in night 3 under 15 mg (r= 0.76, P< 0.05). Taking the overall trend, both slow wave sleep and REM latency appear to be positively (though nonsignificantly) correlated with plasma levels, whereas percentage REM sleep tends to correlate nega- tively. A multiple regression analysis of both plasma levels on sleep parameters did not yield any significant results.

Even±n9 and morning questionnaires

Subjective ratings of mood and fatigue before and after sleep recording under medication did not differ from baseline values. The same applies to subjective sleep ratings, with the single exception of significantly impaired subjective sleep quality after the first night under 30 mg dexfenfluramine. However, by the end of the third night, sleep quality ratings had normalized.

Discussion

Within the therapeutic dose range, dexfenfluramine has few acute effects on sleep, resembling those observed in

racemic fenfluramine. Most parameters relevant to sleep quality remain unchanged. Thus, among anti-obesity agents, dexfenfluramine appears to be much less harmful to sleep than, for instance, d-amphetamine, which causes profound impairment of sleep. However, a conclusive statement on the absence of drug effects on sleep would require a greater statistical power of the data than could be yielded in the present investigation.

In light of the close relationship between CNS serotoninergic systems and sleep regulation, stronger effects of dexfenfluramine on sleep than those observed in the present study could have been expected. A tentative explanation may be provided by the finding that dexfen- fiuramine acts preferentially on 5-HT1 sites in the brain of rats, whereas its main metabotite, d-norfenfluramine, is more active at 5-HT2 binding sites (Garattini et al. 1987). Both receptor subtypes apparently mediate different (and partly antagonistic) effects on sleep (Id- zikowski et al. 1986; Dugovic and Wauquier 1987). Thus, it appears possible that effects of dexfenfluramine may be partly counteracted by its metabolite. However, the present state of knowledge on differential effects of 5-HT receptors on sleep is far from conclusive, apart from clear evidence of strong slow wave sleep stimulation by the pure 5-HT2 receptor antagonist ritanserin (Id- zikowski et al. 1986).

Self-ratings of mood and fatigue under medication did not point to stimulating effect or elevation of mood. For racemic fenfluramine, a similar side-effect profile has been described, in sharp contrast to other anorectic agents (Saletu 1976). According to its pharmaco-EEG profile, dl-fenfluramine was classified with the sedative psychoactive drugs by Fink et al. (1971) as well as Salem et al. (1977). The same observations have also been made in cats (Foxwell et al. 1969). Sudden discontinuation of treatment with d/-fenfluramine has been reported to cause depressive symptomatology (Lewis et al. 1971).

The morning questionnaire ratings showed only a transient impairment of subjective sleep quality under 30 mg. However, this result (being the only significant one of 28 comparisons) may also represent a statistical artifact. Parrott et al. (1980) have demonstrated that dl-fenfluramine may have different effects on subjective sleep in different subjects, with some individuals respond- ing to fenfluramine as a stimulant, and still others as a sedative. In contrast, d-amphetamine has been consis- tently perceived as stimulating and as impairing sleep quality.

Regarding the action of dexfenfluramine on REM sleep, our results corroborated the findings of Firth et al.

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(1970) wi th d / - fenf luramine: a l eng then ing o f R E M latency (signif icant for the 30 m g cond i t i on only) was no t a c c o m p a n i e d by a r educ t ion in the pe rcen tage R E M sleep or changes in any o f the o ther R E M sleep p a r a m - eters (i.e., R E M densi ty , d u r a t i o n o f first R E M per iod) . Thus , the effect o f dexfenf iu ramine (in the t he rapeu t i c range) on R E M sleep is m a r k e d l y different f rom tha t o f an t idep re s san t s which lead to a r educ t ion in this s leep stage, I t is i m p o r t a n t to no te tha t d a t a f rom studies on d / - fenf luramine p o i n t to a dose dependency o f this effect. Tha t is, R E M sleep suppress ion migh t occur in doses exceeding the t he rapeu t i c range. The surpr i s ing f inding o f an ini t ia l bu t t r ans ien t r educ t ion o f R E M la tency u n d e r the sub the rapeu t i c dosages o f 3 m g a n d 7 m g (signif icant for 3 mg only) m a y very well be casual in na ture . However , t oo l i t t le is k n o w n as yet a b o u t the effects o f p s y c h o t r o p i c drugs on sleep p a r a m e t e r s when adminis - te red in very low doses.

W i t h respect to the hypo the t i c a l r e l a t ionsh ip be tween R E M sleep suppress ion a n d an t i dep re s san t ac t ion, a p r o n o u n c e d an t i dep re s san t effect o f dexfenf lu ramine resembl ing tha t o f "c lass ica l" an t idepressan t s is no t expected wi th in the dosage range used in an t i -obes i ty the rapy .

Acknowledgements'. The authors wish to thank Ser~der Forschung und Pharma- Entwicklung GmbH, Miinchen, Germany, and In- stitut de Recherches Internationales Servier (I.R.I.S.), Courbevoie, France, for kindly supporting this study and for determining plasma concentrations of dexfenfluramine and d-norfenfluramine.

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