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REVIEW

Sleep Deprivation Therapy H. Kuhs and R. T611e

This review reports, with as much detail as possible, on the literature relating to therapeutic sleep deprivation (or induced-wakefulness therapy) since it was first described in 1971. The antidepressive effect of sleep deprivation has been substantiated by numerous studies. A series of clinical predictors of response to sleep deprivation are also described. Partial sleep deprivation late in the night is equivei.ent to total sleep depri"ation in terms ~f therapeutic value and--because of its simpler application--can be regarded today as the sleep deprivation method of choice. The status of sleep deprivation in the overall treatment schedule for depressive disorders is discussed in detail. Numerous findings, some of them contraxlictory, have been published on the effect of sleep deprivation on b i~,h~gica,ivariables. To &ae, no unequivocal explanation has beenfound for the mechanism of action ~'sleep deprivation.

Introduction Following case observations by Schulte (1966), Pfiug and T611e (1971a, 1971b) were the first to provide evidence of the antidepressive effect of sleep deprivation (SD) (or inducedwakefulness therapy) for one night in depressive patients. Since then, clinical and I~heoretical interest in therapeutic SD has increased worldwide. SD has proved to be :,m easily applied form of antidepressive therapy. Moreover, because of the acute response to SD, this method lends itself as a model for research into the basic mechanisms of action underlying antidepressive treatment. There has been a marked increase in the number of papers on therapeutic SD sinc~:;a survey by Gillin (1983) and our own study, published in German (Kuhs and T6iie 1986). More recent reviews have been devoted to selective aspects of the subject (e.g., van den Hoofdakker and Beersma 1988; Wu and Bunney 1990). The objective of the present review is to report in as much detail as possible and independently of hypothetical premises on the extensive literature on therapeutic SD and furthermore to draw attention to contradictory and empirically unproven findings as well as to open questions. SD in healthy subjects should be discouraged. A n t i d e p r e s s i v e Effects o f O n e N i g h t ' s S l e e p D e p r i v a t i o n In their original study, Pflug and TSlle (1971a) ascertained a considerable short-term antidepressive effect of one single total sleep deprivation (TSD) in endogeneously de-

From the Department of Psychiatry, University of Milnster, MOnster, Germany. Address reprint requests to Pziva~czent Dr. Hubert Kuhs, Department of Psychiatry, University of MOnster, Albert-SchweitzerStrasse 11, D-4400 MOnster, Germany. Received June 28, 1990; revised October 27, 1990. © 1991 Society of Biological Psychiatry

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pressed patients. The morning difference (SD day versus day preceding SD) was 37.2% according to objective ratings. More than two thirds (69.5%) of patients displayed a moderate or marked improvement (of 21%-40% or of 41%-60%, respectively, compared with the baseline values). Similar results were published by Bojanovsky et al (1973), Pflug (1973), and Rudolf and T611e (1978a). A survey by Wu and Bunney (1990) of 61 studies found a marked antidepressive SD effect among 59% of patients. The antidepressive effect of SD is only slight or even negligible in approximately one fourth to one third of endogenously depressed patients. On the other hand, SD rarely leads to an increase in depressive mood. During the early morning hours (2:00-6:00 hr, known as the c,'itical time), some patients complain of uncharacteristic malaise, vegetative symptoms, and fatigue (Ptiug and T611e 1971a, 1971b; Pflug 1976; Rudolf and T611e 1978b; Zimanova and Vojtechovsky 1974). Headache is also reported, but less frequently (Bhanji and Roy 1975). Continuous registrations of well-being show that responders and nonresponders differ in their mood from 4:00 hr onwards (Hang and Fiilmdrich 1988; half-hourly measurements) or from 5:00 hr onwards (Roy-Byme e~ al 1984a; 2-hourly measurements), whereas no turning point in well-being can be detected. According to Haug and Fiilmdrich (1988), no distinct decrease in depressive mood occurs in responders until after 7:00 hr. The following symptoms are especiallyfm,orably influenced by SD: depressive mood, suicidal tendencies, and psychomotor inhibition (Pfiug and T6Ue 1971a, 1971b; Cole and M ~ e r 1~76; Wasik and Puchala 1978; Svendsen 1976; van den Burg and van den Hoofdakker 1975; Larsen et al 1976). Pflug (1976) found more favorable SD effects on mood than on psychomotor di~,turbances. A therapeutic SD effect on the thought content of depressive patients was also ascertained (Kraft et al 1984). SD is reported to result in a considerable increase in psychomotor agitation in nonresponders (Kasper et al 1988a). A preceding typical diurnal variation in mood (morning low) undergoes intensification or reversal in one third of cases or remains unchanged (Rudolf and T6lle 1978a). In patients without diurnal variations in mood, SD rarely has any effect on the circadian rhythm of their well-being, whereas a typical or an alternating diurnal variation in mood occurs in one sixth of cases (T611e and Goetze 1987). In cases of inverse diurnal variations in mood (evening low) SD generally gives rise to a typical diurnal variation. In responders (according to self-rating), SD induces an increase in subjective energetic arousal and a decrease in tense arousal (van den Hoofdakker et al 1989; Bouhuys et al 1990a). Bouhuys et al (1990b) also studied the influence of SD on vocal parameters in depressive patients. A relapse frequently occurs on the 2rid day after SD, i.e., subsequent to a full night's sleep. The extent of exacerbation is reported to be closely linked with the intensity of the initial SD effect (Roy-Byme et al 1984a). Simultaneous antidepressive pharmacotherapy reduces the risk of relapse, which stands at 83% without or 59% with pharmacotherapy (Wu and Bunney 1990). According to Elsenga and van den Hoofdakker (1983a), antidepressive pharmacotherapy even prevents relapses on the 2nd day after SD. Studies of longer-terra courses of treatment show, however, that a mood setback is to be expected on average subsequent to a full night's sleep even in cases of simultaneous antidepressive medication (Holsboer-Trachsler and Ernst 1986; Dessauer et al 1985). Attempts have also been made to prevent relapses by limiting the amount of sleep in the night subsequent to SD. In contrast to encouraging preliminary results (van Bemmel and van den Hoofdakker 1981), further studies by Elsenga et al (1990) indicate that relapses occur at the same rate with unlimited (23:00-8:00 hr) and limited sleep (23:00--3:00 hr or 4:00-8:00 hr) in the night subsequent to SD. In comparison, a study by Sack et al (1988a) indicates

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that an increasing stab'dization of well-being is induced by two partial sleep deprivations (from 2:00 hr onwards) on consecutive days (cf. Southmayd et al 1985). Besides relapse, improvements in well-being on the 2nd day after SD despite an absence of immediate effect on the first day (so-called day-2 responders) have also been reported. Whereas short-term changes in mood on the 1st and 2nd day after SD can hardly be explained by concurrent pharmacotherapy, other simultaneously applied antidepressive measures have to be taken into account when assessing medium-term and long-term effects of one night's sleep deprivation (Goetze 1981; Philipp 1978; Svendsen 1976). Reports have also been made of almost complete (Rudolf and T611e 1978a; Schilgen and T6ne 1980) and sustained remissions (i.e., dischargeability, Svendsen 1976; cf. also Mfiller and Fialho 1974; Sidorowicz I976). When comparing SD effects, it is important to remember that the criteria applied in recording them vary considerably, particularly with respect to selection of the assessment instrument (qualitative or semiquantitative global rating scales, standardized observer scales, and self-rating scales). Examples are short forms of the Hamilton Rating Scale for Depression (Hamilton 1960; Bojanovsky and Clfloupkova 1966), the Visual Analogue Mood Scale (Aitken 1969), the scale of the subjective feeling of well-being (yon Zerssen et al 1970), and the Mtinster Polarity Profile (G~etze 1984). Secondly, for adequate timing of the measurement~ the following has to be taken into consideration: As SD may influence the diurnal rhythm of mood (see above), one single measurement per day before and subsequent to SD (morning or evening difference) does not reflect the therapeutic result with sufficient accuracy. This problem can be overcome by recording two measurements per day (morning and evening) and computing the so-called mean daily difference (Rudolf and T611e 1978a). It is moreover advisable for the measurements to be continued until the 2nd day after SD. Patlial Sleep Deprivation The antidepressive effec; of partial SD late in the night (PSD-L) is comparable with TSD; the mean daily diff~;rence is 30.1% according to Schilgen and T611e(1980). Affective disturbances undergo a more distinct improvement than somatic complaints. The introduction of PSD has brought about a marke0 improvement ~ SD tolerance; the reduced interval of wakefulness represents a considerable relief to patients. The arousal time selected in the initial studies was 1.30 hr, as both the turning point in mood, based on experience with TSD, and the nocturnal minimum of essential psychophysiological parameters (rectal temperature--Goetze and T611e 1987; heart rate and systolic blood pressure--Rudolf and T611e 1977) occur later in the night, i.e., after 2:00 hr. PSD from 2.30 hr onwards is reported to have virtually the same effect as PSD starting at 1:30 hr (Fischer et al 1990a). Investigations by Elsenga and van den Hoofdakker (1983b) indicate that a less favorable effect is to be expected with PSD-L when the waking time is 3:00 hr or later. Further systematic studies on ~e influence of arousal time on PSD effect have to be carded out. Partial SD early in the night (PSD-E), i.e., up to 1:30 hr, has a distinctly less marked antidepressive effect than TSD and PSD-L (Goetze and T611e 1981). Thc~e results have been confirmed by Elsenga et al (1988); the authors found more favorable therapeutic results with PSD-L (sleep from 20:00 to 23:00 hr) than with PSD-E (sleep from 2:00 to 5:00 hr). Accordl.ng to a crossover study (Sack et al 1988a), two successive PSD-L (sleep until 2:00 hr) are superior to twice PSD-E (sleep from 2:00 hr onwards; cf. Parry and

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Wehr 1987). Total sleep time and proportion of REM sleep (REM%) were distinctly shorter with PSD-L than with PSD-E and were all the more marked in PSD-L responders the more favorable the SD effect was (Sack et al 1988a).

Sleep Deprivation and

Naps

From the first experiences with SD therapy, relapses have been reported subsequent to naps on the SD day. Single-case studies (Knowles et al 1979; Roy-Byme et al 1984a) suggest that the effect of SD can be reversed by evea brief naps. The effect of naps obviously depends on the preceding effect of SD: In SD nonresponders, naps have no influence (Wiegand et al 1987a) or even a favorable influence (Gillin et al 1989) on moo'~l, whereas in SD responders naps generally trigger an immediate relapse lasting until the evening of the SD day (Wiegand et al 1987b). Polysonographic recordings indicate that a relapse subsequent to naps is linked with the occurrence ef REM sleep but is also related to the length of the naps (Wiegand et al 1987a; cf, Wu and Bunney 1990). Another study, in contrast, reports a depressiogenic effect of naps on the SD day independent of the occurrence of REM sleep (Riemann et al 1988). The sleep architecture of naps ca the SD day and that of nocturnal sleep prior to SD are reported to be largely similar; this applies in particular to a shortened ItEM letency (Berger and Wiegand 1987; Elsenga et al 1987). Repeated Sleep Deprivation Therapy SD is frequently applied repeatedly in the course of antidepressive therapy. The results of SD therapy without concomitant antidepressive drugs are contradictory. Two TSD at a 2-day interval had only slight effects according to van den Burg and van den Hoofdakker (1975), while thvorable SD effects were reported by others (Kvist and Kirkegaard 1980; Zander et al 1981; Manthey et al 1983). Repeated SD application leading to a decline in antidepressive effect [comparable with a tolerance development (Roy-Byme et al 1984a)] could not be confirmed. Performance of Sleep Deprivatio~ Therapeutic SD wa~ initially carried out with inpatients only. SD can also be performed on an outpatient basis, provided that the patients are familiar with the method (Pflug 1972; Voss and Kind 1974). Treatment in groups has proved successful in the psychiatric hospital; the patients are offered a range of activities (sports, meals, games). This procedme ni~es it e~icr for patients to stay awake at night but has no influence on the antidepressive effect (,f SD (Fischer et al 1990b). Changes in physical activity or posture do not contribute to SD success, as is indicated by favorable results in patients staying in bed throughout the SD procedure (Baumgarmer and Sucher 1990). However, Wehr (unpublished observation) found that SD is more effective in cold ambient temperature than in warm ambient temperature. The SD effect is also independent of psyc,~o!ogical factors such as therapist-patient relationship, personality traits of the patient, and the therapist's and patient's expectations (Buddeberg and Dittrich 1978). The last-mentioned finding is confixmed by the fact that SD was carried out initially under blind conditions (Pflug and T611e 1971a), whereas equivalent results were achieved in open studies performed later (cf. Roy-Byme et al

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1984a; Post et al 1987; Wu and Bunney 1990). Nevertheless it is difficult to rule out the possibility of observer bias rigorously, because an appropriate placebo control for SD is impossible.

Side Effects and Tolerance of Sleep Deprivation Fatigue and vegetative symptoms in the early morning hours were discussed above. Apart from these, side effects of SD therapy are extremely rare: Therapeutic SD may, especially in bipolar affective psychoses, result in a switch into hypomanialmania (Kretschmar and Peters 1973; van Scheyen 1977; Zimanova and Vojtechovsky 1974; Cole and Mfiller 1976; Bhanji and Roy 1975; Vovin et al 1979; Dessauer et al 1985; Roy-Byrne et al 1984a; Pflug 1976; Knowles et al 1979; Stoddard et al 1977). Provocation of psychotic states by SD is reported only rarely in patients with depressive disorders (Kretschmar and Peters 1973; van Scheyen 1977; Bhanji and Roy 1975; Pflug 1976; van den Burg and van den Hoofdakker 1975). Seizures were observed to be triggered in cases of preexisting epilepsy or of simultaneous medication withdrawal. SD therapy can be regarded as virtually free of complications and risks.

Dependence of Sleep Deprivation Effect on Type of Depression The majority of authors agree that the effect of SD is all the more unfavorable the more the illness deviateb from the classical "endogenous" depressive syh~lrome (RoyByrne et al 1984a). Some authors ascertained irregular and minor SD effects in neurotic depression (e.g., Pflug and T611e 1971a: morning difference 7.9% compared with 37.2% in endogenous depression; of. Nieto et al 1980; Lit 1979; MOiler and Fialho 1974; Sydor 1985). On the other hand, therapeutic results in severe neurotic depressive states with vital symptoms are considerably more favorable (Rudolf and T611e 1978a: morning difference 40.3%). In a review covering 61 studies, Wu and Bunney (1990) determined a response rate of 67% in endogenous depression compared with 48% in neurotic depression. The course of depression (unipolar, bipolar) has no influence on SD response (TSD: Larsen et al 1976; Pflug 1976; Gerner et al 1979; Svendsen 1976; Elsenga and van den Hoofdakker 1987; Kasper et al 1988a; Baumgarmer et al 1990a; PSD-L: Schilgen and T611e 1980). Exceptionally favorable SD effects were, however, observed in bipolar depression by Fiihndrich (1981). SD effects are reported not to differ between single and recurrent depression (Elscnga and van den Hoofdakker 1987). In rapid cyclers, in the majority of cases SD triggers a switch into mania.~hypomania (Wehr et al 1982) but can be used for therapeutic and prophylactic purposes too, as preliminary findings covering small numbers of patients suggest (Lovett-Doust and Christie 1980; Churchill and Dilsaver 1990; Christodoulou et al 1978; Papadimitriou et al 1981). Sleep Deprivation in Other Than Depressive Disorders Parry and Wehr (1987~ reported favorable SD effects in patients with a premen~.~.ual syndrome (late luteal phase dysphoric disorder). Patients with a schizophrenic and schizoaffective psychosis suffering from postrem-

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issive depressive states also benefit from SD therapy (TSD: Fiilmdrich 1982; PSD-L: H6chli et al 1985; Holsboer-Trachsler and Ernst 1986). Obviously the effect of the SD is independent of the type of schizophrenia; psychopathological predictors of response could not be ascertained (F~mdrich 1982). TSD is virtually ineffective in patients with panic disorder (Roy-Byrne et al 1986) and with obsessive-compulsive disorder (Joffe and Swinson 1988). No effect can be detected on anxiety or obsessive-compulsive symptoms or on any depressive symptomatology. TSD is also ineffective in primary degenerative dementia, even with coexisting depressive symptoms (Buysse et al 1988; Letemendia et al 1986). According to a preliminary report by Bertolucci et al (1987), in long-term Parkinson's disease TSD has a positive influence on rigor and akinesia but not on tremor. Psychopathological Predictors of Response to Sleep Deprivation Attention has been given to the influence of diurnal variations in mood on SD effect. Although Pflug (1976) and Waldmann et al (1979) claim that diumal variations in mood are of no prognostic significance, most authors detected an excepfion~Aly favorable SD response in cases of preexisting typical diurnal variations in mood (moming low: RoyByrne et al 1984a; Cole and Mtiller 1976; van Scheyen 1977; Elsenga and van den Hoofdakker 1987). According to Reinink et al (1990), patients with predominantly typical diurnal variations in mood exhibit the best TSD results, regardless of whether such variations in mood are to be detected on the day preceding SD. In cases of preexisting typical diurnal variations in mood, SD prevents a mood setback the next moming, so that exceptionally favorable SD effects, based on the morning difference, have been observed in these cases (Rudolf and T611e 1978a). An inverse diumal variation in mood (evening low), in contrast, is generally ineffective or has a negative SD effect (Elsenga and van den Hoofdakker 1987). Such observations have led to the assumption that sleep reverses the preexisting diurnal variation in mood, whereas SD counteracts this reversal of mood (van den Hoofdakke~ ~tl Beersma 1988). Typical diurnal variations in mood proved to be only a slightly positive predictor of PSD-L effect (Schilgen and T611e 1980); they are reported to predict an unfavorable effect of PSD-E (Goetze and T611e 1981). Depressive vital symptoms have been examined only sporadically in the context of SD. They are reported to predict a favorable effect of TSD (Rudolf and T6ile 1978a) but not of PSD-L (Schilgen and T611e 1980). Exceptionally ~tvorable TSD results have also been reported in the presence of both typical diurnal variations in mood and vital symptoms (Rudolf and T611e 1978a). Psychotic features, in particular delusions, were found to be of favorable (Elsenga and van den Hoofdakker 1987), unfavorable (Kasper et al 1988a), or of no predictive value (Fihndrich and Hang 1988) for SD response. Psychomotor inhibition has been associated both with a favorable (Larsen et al 1976; Vovin and Fakturovich 1985) and an unfavorable SD effect (Kvist and Kirkegaard 1980; FiUmdrich 1981). An exceptional!y favorable response to SD has been reported in patients suffering from mark~ sleep dism ,bances (Roy-Byme et al 1984a; but compare with EEG findings outlined below). Bouhuys et al (1985, 1989) studied the significance of arousal phenomena for SD efficacy, finding that observed behaviors that were related to arousal (especially selfmanipulative hand movements) could predict SD response.

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Dependence of Sleep Deprivation Effects on Age, Severity of Depression, and Sex The SD effect appears to be independent of age (Holsboer-Trachsler and Ernst 1986; Elsenga and van den Hoofdakker 1987; Bhanji and Roy 1975; Bhanji et al 1978; Ffihndrich 1981; Gerner et al 1979; Kvist and Kirkegaard 1980; Svendsen 1976; Baumgartner et al 1990a). There have also been reports of explicitly favorable SD effects in elderly patients (Rudolf and T611e 1978a; Schilgen and T6lle 1980; P0hringer et al 1978; Cole and Mfiller 1976; Richard et al 1982). However, Pllug (1978) recorded a better response among young patients than among elderly depressive patients. In a single-case study, King et al (1987) drew attention to SD therapy in children. SD is effective in depressive states of varying severity (Kasper et al 1988a; Pflug and T611e 197Ja; van den Burg and van den Hoofdakker 1975; Bhanji et al 1978; Kvist and Kirkegaard 1980). As expected, more favorable SD effects were observed in severe th~rj in mild depressions (Zimanova and Vojtechovsky 1974; Post et ",d 1976; Duncan et 1980; Rudolf and T611e 1978a; Schilgen and T611e 1980). A brief CluTent depressive episode has been claimed to indicate an exceptionally favorable SD effect (Rudolf and T611e 1978a; Schilgen and T611e 1980; Vovin and Fakturovich 1985); this finding has not, however, been confirmed by other authors (Bhanji and Roy 1L975;Bhanji et al 1978; Elsenga and van den Hoofdakker 1987; Holsboer-Trachsler et al 1988). Roy-Byrne et al (1984a) found that the effectiveness of SD is in line with the severity of the overall course of the illness (number of previous depressive episodes, total duration of the illness). This correlation was not confirmed by other authors (Bhanji and Roy 1975; Bhanji et al 1978; Svendsen 1976; Elsenga and van den Hoofdakker 1987). The effect of SD is independent of sex (Bhanji and Roy 1975; Bhanji et al 1978; Ffihndrich 1983; Gerner et al 1979; Kvist and Kirkegaard 1980; Larsen et al 1976; Pflug 1976; Svendsen 1976; Elsenga and van den Hoofdakker 1987).

Sleep Deprivation in Combination With Antidepressive Pharmacotherapy In most cases repeated SD therapy is combined with antidepressive pharmacotherapy (Bhanji and Roy 1975; Pflug 1976; Lar~en et al 1976; Richard et al 1982; Wasik and Puchala 1978; Vovin and Fakturovich 1985; Waldmann et al 1979; cf. Sidorowicz 1976). Repeated PSD-L at 2-day (Holsboer-Trachsler and Ernst 1986) and 5-day (Dessauer et al 1985) intervals effected a scalariform treatment course° Each SD has (on average) a distinct antidepressive effect that declines after a recovery night until the next SD triggers off further amelioration. Two SD sessions per week seem to be more effective than only one per week (Svendsen 1976). However, no systematic s~Jdies have been performed as yet to determine the most favorable interval between the SD treatments. Contradictory results have been reported as to whether the effect of the first SD predicts the overall SD success (Holsboer-Trachsler et al 1988; Vovin e~| Fakturovich 1985) or not (Fahndrich 1981; Zander et al 1981; cf. Telger et al 1990).

The States of Sleep Deprivation in the Overall Treatment Schedule The efficacy of antidepressive pharmacotherapy is enhanced by combination with TSD: Clomipramine in combination with one single (Loosen et al 1976) or repeated TSD (Elsenga and van den Hoofdakker 1983b) induces more rapid remission than pharmao

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cotherapy alone. Similarly, Holsboer-Trachsler and Ernst (1986) observed more favorable SD effects in patients with than in those without me~'cation. In contrast, SD alone (without any concomitant antidepressive treatmen0 is not recommendable. However, a systematic comparison of antidepressant medication and repeated TSD (plus placebo) yielded similar therapeutic results (Elsenga and van den Hoofdakker 1983a). In cases of so-called therapy-resistant (drug-refractory) depression, application of SD as an additional therapy is promising (Bhanji and Roy 1975; yon Scheyen 1977; Sidorowicz 1976; Wasik and Puchala 1978; Marc.hey et al 1983; Nosachev 1985). Combined therapy with antidepressive medication and repeated SD proved just as favorable in drugrefractory depressive patients as antidepressive therapy alone in a non-drug-refractory control group (Dessauer et al 1985). Promising SD effects have been observed even after unsuccessful electroconvulsive therapy (van Scheyen 1984; cf. Lit 1973). Combination of SD and lithium (Baxter et al 1986) has a more sustained antidepressive effect (up to the 5th day after SD) than SD alone. Combination of SD and bright-light therapy (3000 lux) is accompanied by a faster remission than SD therapy in a dim room (1 lux), with the overall antidepressive effect being similar (Wehr et al 1985). That light is rather of subordinate significance for therapeutic SD is suggested by the lack of any seasonal variation of SD effect (Elsenga and van den Hoofdakker 1987). In a crossover study, however, bright-fight therapy (2200 lux for 3 hr/day for 5 days) proved to be just as effective as two PSD-L applications at a 2-day interval (Heim 1988). It can be presumed that the short-term effects of SD might be related to the longerterm effects of other antidepressive therapeutic measures (cf. Post et al 1987). A favorable SD response was found to be a predictor of successful therapy with antidepressive medication (Wh-z-Justiec e: ~ 1979; Philipp and Wemer 1979) or with carbamazepine (RoyByme et al 1984b). According to others there is no relationship (Amin 1978) or a negative relationship (H6chli et al 1986; Riemann and Berger 1990) between SD response and response to antidepressiw ~ags. Due to methodologicas reasons, inconsistent results have also been reported on the predictive value of SD for the choice of the most effective antidepressant (Wirz-Justice et al 1976; F~hndrich 1983).

Neurobiological Correlates of Sleep Deprivation Effects Numerous biological variables have been investigated in connection with SD therapy.

The biochemical, neuroendocrinological, neurophysiological, and psychophysiological investigations reviewed in this article deal essentially with the following issues: What are the immediate changes caused by SD? Is there a relationship between any changes in biological parameters and SD response? Are there any biological predictors of the SD effect?

Biochemical Studies The assumption that SD influences the adrenergic, dopaminergic, and serotonergic mechanisms (Mouret 1982) has given rise to a series of biochemical investigations: SD induces a distinct increase in noradrenaline (NA) and vaniUin mandelic acid (VMA) excretion and in urinary NA/adrenaline (A) and NAldopamine (DA) quotients in re-

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sponders compared with nonresponders (Matussek et al 1974). The investigation periods comprise SD night versus the night before SD as well as SD night and subsequent day versus a 24-hr interval before SD. The findings indicate stronger activation of the peripheral sympathetic system with favorable than with unfavorable SD effect. In day-2 responders the stated biochemical changes occur in the night following SD (Loosen et al 1974). SD has no significant influence on the adrenal medulla (A). In contrast, Nosachev et al (1988) found increased A and decreased NA excretion after SD. DOPA excretion also decreased after SD. The excretion of 3-methoxy-4-hydroxy-phenylglycol (MHPG), which, in contrast to NA, is partly of central nervous system origin, is not changed significautly by SD (Matussek et al 1977), irrespective of the SD response. Post et al (1976) and Gemer et al (1979) recorded a decline in MHPG in the cerebrospinal fluid (CSF) among responders but an increase among nonresponders. An increased urinary NA/A ratio (Matussek et al 1974) and an elevated CSF NA level (Roy-Byrne et al 1984a) are predictors of a favorable SD response. Similarly, increased urinary (Mamssek et al 1977) and CSF MHPG (Post et al 1976; Gemer et al 1979) indicate a favorable SD effect. Amin et al (1980), however, failed to confirm this finding. This discrepancy is---at least in part--due to different sampling periods in the studies compared. In contrast to their MHPG findings, Gemer et al (1979) reported a rise in homovanillic acid (HVA), a DA metabolite, in responders. According to Gemer et al (1979), SD responders had lower baseline levels of CSF HVA than nonresponders, whereas Post et al (1976) found that HVA has no predictive value for SD response. CSF 3-hydroxyindoleacetic acid (3-HIAA), a serotonin metabolite, undergoes no significant change as a result of SD (Post et al 1976; Gemer et al 1979; van Scheyen 1977), nor is 5-HIAA of predictive value for SD response. Monoamine oxidase (MAO) is not influenced by SD either OVirz-Justice et al 1976; F~mdrich 1986). A rise in MAO after SD is claimed to be accompanied, however, by a favorable response to subsequent maprotiline therapy, while a fall in MAO predicts a favorable clomipramine response (F~mdrich 1986). The affinity and density of imipramine binding sites (known to modulate the reuptake of serotonin from the synaptic cleft) are claimed to be predictive of SD response: However, they are changed in the same direction by SD in responders and nonresponders (Hang et al 1988). The following electrolyte changes during SD therapy have been described (Bojanovsky et al 1974): increase in extracellular potassium (serum), decrease in intracellular potassium (erytin-ocyte), and decrease in chloride and increase in calcium (serum). Gemer et al (1979) recorded a fail in CSF calcium in SD responders but a rise in nonresponders. A fall in hematocrit under SD was recorded by Bojanovsky et al (1974). There have also been sporadic reports during SD on serum tryptophan (Wirz-Justice et al 1979; Schmocker et al 1975), cyclic adenosine monophosphate (cAMP) (Numata et al 1980), and serum tyrosine (Schmocker et al 1975).

Neuroendocrinological Studies Neuroendocrinological SD examinations have focused on the hypothalamic-pituitaryadrenal or hypothalamic-pituitary-thyroid system. SD causes a rise in urinary cortisol (Goetze and T611e 1987; Bouhuys et al 1990a) and in serum cortisol (Yamaguchi et al 1978; Baumgartner et al 1990b). This effect was

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found to be partly independent of SD w~ponse (Bouhuys et al 1990a), partly exceptionally marked in SD responders (Yamaguctd et al 1978; Baumgartner et ~ 1990b). Gerner et al (1979) recorded a rise in serum cortisol on the SD day among responders, but a fall among nonresponders. Comparison of the data is complicated by differences in the methods of evaluating response to SD and by different sampling techniques. Some findings suggest that SD results in a phase advance of the circadian urinary cortisol rhythm (Bouhuys et al 1990a, measurements at 3-hr intervals). However, the authors did not find a relationship between the cortisol shift and the mood response to SD. No phase shift of the urinary cortisol excretion (or any change in peri,.,d length) was recorded by Goetze and T611e (1987, measurements at 4-hr intervals) or by Yamaguchi ct al (1978, serum cortisol measurements at 4-hr intervals). Goetze and T611e (1987) did, however, determine an increased cortisol amplitude on the SD day. Obviously urinary cortisol is not a predictor of SD effect (Bouhuys et al 1990a; Roy-Byme et al 1984a). SD thc~py leads to gradual normalization of the dexamethasone suppression test (DST) results (Nasrallah et al 1980; van Scheyen 1984; Holsboer-Trachsler and Ernst 1986). However, in endogenous depressives only the variance of DST results (so-called cortisol response) is increased after one single SD therapy, regardless of its effectiveness (Kasper et al 1983; Kuhs 1985). This finding can be interpreted as an expression of the increasing instability of the adrenocortical system under SD. In preliminary reports DST was assumed to be of predictive value for the SD response: According to Nasrallah and Coryell (1982), King et al (1982), Lee and Taylor (1983), and Trachsler et al (1985), dexamethasone nonsuppression is accompanied by a favorable SD effect, whereas Joffe et al (1984) reported a favorable SD effect with dexamethasone suppression. Further studies including larger patient samples (Holsboer-Trachsler and Ernst 1986; Kuhs 1985), however, have failed to confirm a correlation between DST results and predicted SE response. The majority of authors reported an increase in thyroid hormone concentrations (T3, free T3, T4, free T4) under SD (Baumgartner et al 1990a, 1990b; Kaschka et al 1989). Con,.entrations of thyroid-stimulating hormone (TSH) also increase under SD therapy (Baumgartner et al 1990a, 1990b, 1990c; Kasper et al 1988b; Kaschka et al 1989); this finding was not, however, confirmed by Sack et al (1988b) among rapid cyclers. The increase in thyroid hormone concentrations occurs between 24:00 and 2:00 hr in the SD night (Baumgartner and Hang 1988), thus preceding the change in mood. Responders to SD had higher thyroid hormone levels before SD than nonresponders (Baumgartner et al 1990a, 1990b). A positive correlation between increased TSH concentrations and SD effect has also been reported (Baumgartner et al 1990a) but could not be confirmed in the majority of studies (Kasper et al 1988b; Kaschka et al 1989; Sack et al 1988b; see also Baumgartner et al 1990b, 1990c). Whereas m~ximum nocturnal urinary melatonin excretion is not influenced by SD (Jimerson et al 1977), SD prevents a nocturnal increase i~ ~ n ~ prolactin; changes in prvlactin secretion are unconnected with SD response (Kasper et al 1988b; Baumgartner et al 1990b). Growth hormone (GH) concentrations are presumably enhanced in responders during SD (Baumgartner et al 1990b); the authors found no correlation between GH concentration and clinical response. Interpretation of these data is, however, restricted by the small number of patients involved. There has also been a report about a significant decrease in testosterone during SD, while no changes were observed for LH, FSH, and estradiol (Baumgartner et al 1990a). Further studies on these hormones under SD therapy have not been conducwA so far.

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Neurophysiological Studies A number of studies have investigated the correlation between EEG sleep parameters and therapeutic SD: Improved sleep continuity in the recovery night is reported by Papousek (1978), Riemann and Berger (1990), Airapetov (1984), and Ve~, and Airapetov (1984) for responders and nonresponders, but by Duncan et al (1980) and Reynolds et al (1987) for SD responders only. According to some authors (Papousek 1978; Riemann and Berger 1990; Duncan et al 1980; Airapetov 1984; Vein and Airapetov 1984), ~ e proportion of delta-sleep increases after SD in all patients, but according to Reynolds et al (1987) and Gillin et al (1989) only in responders. R~I/I latency is prolonged in the night after SD in re,~ponders acc,:~rding to Riemann and Berger (1990) and Duncan et al (1980). On the other h~ad, a R ~ rebound has been recorded in SD responders in the recovery night (Duncan et al 1980). Other authors (van den H~gfdakker et al 1986; GilKn et al 1989; Reynolds et al i987) round no influence of SD on REM sleep parameters. Zander et al (1981) recorded shortened REM latency i~ responders and nonresponders after SD. According to Buysse et al (1988), a distinct REM rebound in the first and second night after SD in depressive pseudodemen~ia permits differentiation from degenerative dementia in almost 90% of cases. These authors claim that the changes in REM sleep parameters correlate in part with the antidepressive efficacy of SD. According to Knowles et al (1981) and Gemer et al (1979), SD has no influence on EEG sleep parameters at all. Some authors have also examined the predictive value of sleep parameters for the at,..~depressive effect of subsequent SD: Riemann and Berger (1990) and Duncan et al (1980) recorded a more disturbed sleep pattern before SD in responders than in nonresponders (in particular shortened REM latency and sleep continuity disturbances). Zander et al (1981), on the other hand, reported shorter total sleep time and longer waking periods in responders than in ~vrzesponders. According to van den Hoofdakker et al (1986), REM latency and proportion of REM sleep (REM %) are not predictive of SD effect. Findings relating to the predictive value of delta-sleep are equally contradictory: According to Riemann and Berger (1990), Duncan et al (1980), and Gillin et al (1989) the proportion of delta-sleep does not differ between responders and nonresponders. According to Reynolds et al (1987), delta-sleep correlates with the predicted SD response; in contrast, a reduced proportion of delta-sleep before SD was found among SD responders compared with nonresponder~ (Zander et al 1981). According to Knowles et al (1981) and G-emer et al (1979), EEG sleep parameters have no predictive value for SD response. The considerable discrepancies of the EEG findings under SD are difficult to interpret: EEG sleep measurements are comparable between most studies, but SD response criteria and the drug-free period before EEG examinations differ. Additionally some of the studies included only small samples sizes. SD is accompanied by an increase in visual evoked potential amplitudes (Buchsbaum et al 1981); a similar finding was recorded by Kasper et al (1988a) for auditory evoked potentials on the nondominant hemisphere in SD responders and on the dominant hemisphere in nonresponders.

Psychophysiological Studies Ps3 chophysiological investigations have concentrated on the influence of SD on heart rate, blood pressure, and body temperature.

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SD resulted in flattening of the pulse curve in endogenous depressives but not in a neurotic depressive control group (measurements at 2-hr intervals; Rudolf and T611e 1977; Rudolf et al 1976). This effect is correlated with SD response. With PSD-E, the reduction in pulse amplitude is less pronounced than with TSD (Goetze and T611e 1981). Circadian measuremem~ over a 5-day period indicated that SD had no influence on the period length and p h ~ position of the pulse curve (Goetze and T611e 1987). According to ophthalmodynamographic measurements systolic blood pressure rises in endogenous depressives after SD (in comparison with neurotic depressives; Pflug and T611e 1971). Inversely, a tendency towards orthostatic dysregulation is to be determined after SD in neurotic depressives but not in endogenous depressives (Bojanovsky et al 1973). Like the pulse curve, the 24-hr blood pressure curve is flattened by SD in endogenous depressives but not in neurotic depressives (Rudolf and T611e 1977; Rudolf et al 1976). Besides a fall in body temperature on the SD day (Pflug et al 1981; oral measurement), continuous rectal registrations showed a rise in minimum temperature in the SD night (Elsenga and van den Hoofdakker 1988), the intensity of which correlates with SD response. There is also a correlation between the fall in noctural minimum temperature and any relapse in the recove~ night (see also Elsenga et al 1990). The data proposed suggest a flattening of the circadian temperature curve during SD. This was also found by Gemer et al (1979; measurements at 2-hr intervals), but only in nonresponders. No significant influence on the phase position and period length of the circadian temperature curve was found (Goetze and T611e 1987). Body temperature has no predictive value for SD response (Gemer et al 1979). Even with a favorable antidepressive effect (in contrast to antidepressants), SD causes a further increase in time estimation errors (Bojanovsky and T611e 1973; Stockmann and Liebner 1988) compared with healthy controls. The following psychophysiological SD effects have also been reported sporadically: increased motor reactivity (Bezzi et al 1981), psychomotor activation (tal~ ing test, Schmocker et al 1975; pedometric activity, Matussek et al 1974; shortening; of the reaction time after auditory stimuli, Sydor 1985), rise in pain threshold (Bezzi et al 1981), increased mydriasis (Bojanovsky et al 1973), and increastxl respiratory rate (Schmocker et al 1975). According to Airapetov (1984), SD normalizes skin galv~lic ~ o n s (for compari~n see Schmocker et al I c 75).

Concluding Remarks on the Mechanism of Action Underlying Sleep Depfi,~ation Tl-~ findings proposed in this survey fail to inuicate a c~ear-cut raechanism of action underlying the antidepressive e~ect of sleep denrivation. Although SD causes a variety of changes in neurobiologic~, variables, predictt,,s of SD me just s~ difhcult tc discern as unequivocal correlations between changes iL oiological pmamet~i~s .',rid SD response Contradictory results are mainly d'~e to methodological d'fferences bezween the studies, as noted above. In some cases it was merely an increasing inambility e,~ biological parameters (e.g., enhanced ccrtisol response) that was recorded_ afte: SD. These findings are interesting and deserve f~rther attention in future SJ~ investigations. In spite of many unresolved problems ;n the coatext of therapeutic SD most authors ~c~ee that both ~be clini,~al and *.bc biolog~,.a~ effects of SD differ between endcgenous depression and other form__s~f depression.

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SD and antidepressive pbarmacotherapy probably involve different mechanisms of action; this is suggested not only by the differences in time course (onset and duration) of the respective antidepressive treatments. Moreover, the influence of SD on some parameters is contrary to that of antidepressants. There are data available from animal studies indicating a lowered activity of the adrenergic locus cemleus in several species, including monkeys, during sleep and an increase in NA activity during wakefulness (for more details see Jacobs et al 1986). The SD findings in depressive patients also point to an activation of the (peripheral) sympathetic system in SD responders (see above). In contrast to antidepressive medication, in therapeutic SD the role of adrenergic (and serotonergic) mechanisms could, however, not be substantiated sufficiently until now. As interesting as data from animi studies may be from a theoretical point of view, caution is required not to apply such findings to SD therapy h~ depressh.,e patients. Among others this is mainly due to the fact that antidepressive p~opet~es of SD/wakefulness cannot be demonstrated in animals. Therefore in this surve~~animal studies are not dealt with in further detail. Clu~nobiological hypotheses, which have been put forward since the first experiences with therapeutic SD, ~annot be dealt with here in detail. The desynchronizatjon hypothesis (Pai~ousek 1975) and the phase-advance hypothesis (Wever 1979; Wehr and Goodwin 1981; Wehr et al 1979) would suggest that therapeutic SD is accompanied by an influence on the phase length or phase position of circadian rhythms. This has yet to be given adequate erapirical substantiation, however. REM sleep characteristics in depressive disorders (including reduced REM latency) and the antidepressive properties of selective REM SD (Vogel et al 1968, 1975) suggested that the efficacy of SD might be related to REM sleep parameters. As noted above, however, to date polysomnographic studies have yielded only equivocal findings. Two further hypotheses are based on the observation that a considerably prolonged period of wakefulness (see TSD) has an antidepressive effect (Borb61y and Wh-z-Justice 1982) while sleep (e.g., naps, recovery night) is generally depressiogenic (Wu and Bunney 1990). Experience especially with PSD indicates that both the duration and the timing of SD are decisive for its antidepressive efficacy. Finally it has to be stressed that a variety of issues inherent in therapeutic SD still warrant further investigation. These comprise both important clinical aspects of 5D (e.g., most favorable arousal time of SD and most favorable interval between the SD treatments) a~,~ the mechanism of act~m underlying SD. Nevertheless the antidepressive properties of SD have bee~ unanimously confirmed in numerous studies. Furthermore SD can be applied easily and is free of serious side effects. Thus SD retains its status as an additional therapeutic measure in the overall treatment schedule of depressive syndromes.

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