Cholinergic REM induction test: Muscarinic supersensitivity underlies polysomnographic findings in both depression and Schizophrenia

J.p~vchiur

Rer.. Vol

Pergamon

28. No

3. pp. 195-210. 1994 Elsewer Science Ltd Prmted I” Great Bntem 0022 -3956,‘94 S7.00 + .OO

0022-3956(94)E0013-G

CHOLINERGIC REM INDUCTION TEST: MUSCARINIC SUPERSENSITIVITY UNDERLIES POLYSOMNOGRAPHIC FINDINGS IN BOTH DEPRESSION AND SCHIZOPHRENIA DIETER RIEMANN, FRITZ HOHAGEN, STEFAN KRIEGER, HORST GANN, WALTER E. MILLER,

ROBERT OLBRICH, HANS-J~RG

HEIDEMARIE Ldw

WARK, MARTIN BOHUS,

and MATHIAS BERGER

Psychiatric Clinic of the University of Freiburg, Freiburg, Germany (Receiced,for

publication

28 March 1994)

Summary-Disinhibition of rapid eye movement (REM) sleep (e.g. shortening of REM latency, heightened REM density) is frequently encountered in patients with a major depressive disorder (MDD). Administration of cholinomimetics prior to or during sleep leads to a more pronounced advance of REM sleep in depressed patients compared to healthy controls and patients with other psychiatric disorders. The present study tested whether the cholinergic REM induction test (CRIT) with 1.5 mg RS 86 (an orally acting muscarinic agonist) differentiates patients with MDD (n = 40) from those with schizophrenia (n = 43) and healthy controls (n = 36). The most pronounced shortening of REM latency after cholinergic stimulation occurred in patients with MDD. However, a significant number of patients with schizophrenia also displayed short REM latencies (REM latency ~25 minutes) under placebo conditions and after cholinergic stimulation. REM density measures more clearly differentiated patients with MDD from those with schizophrenia. It is concluded that a subgroup of patients suffering from schizophrenia displays signs of a muscarinic receptor supersensitivity.

Introduction of REM sleep has been shown to be a replicable and robust finding in major depression (for an overview, see Reynolds & Kupfer, 1987; Gillin et al., 1984). This disinhibition presents as shortening of REM latency (i.e. the time elapsed between sleep onset and the occurrence of the first REM period) prolonged first REM period duration and heightened REM density. The question of the specificity of REM sleep abnormalities for depression compared to other psychopathological groups is now under debate (for a review, see Benca et al., 1992), especially with regard to schizophrenia. There have been an increasing number of sleep studies in schizophrenia in recent years. Zarcone et al. (1987) reported a shortening of REM latency in chronic patients, whereas Ganguli et al. (1987) studying young first-onset drug-naive male subjects were not able to detect REM sleep abnormalities in their patient sample. Recently, Tandon and co-workers (Tandon et al., 1988; Tandon & Greden, 1989; Tandon et al., 1992) confirmed a shortening of REM

DISINHIBITION

Correspondence to: Dr Dieter Riemann, Freiburg. Germany.

Psychiatric

Clinic of the University

195

of Freiburg,

Hauptstr.

5, 79104

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D. REMANN et al

latency in both drug-naive and chronic schizophrenic patients; they postulated muscarinic supersensitivity as the underlying cause for the early onset of REM sleep in this patient group. The cholinergic REM induction test (CRIT, see Sitaram et al., 1984; Berger et al., 1989; Gillin et al., 1991) provides an experimental strategy for evaluating hypotheses of involvement of central nervous cholinergic neurotransmission in REM sleep regulation and different psychopathological conditions. Cholinomimetics administered prior to or during sleep proved capable of hastening the onset of REM sleep (for an overview see Sitaram et al.. 1984) in healthy subjects. Our studies with the muscarinic agonist RS 86 showed a shortening of REM latency after cholinergic stimulation that was much more pronounced in depressed patients than in patients with eating disorders, personality disorders, anxiety disorders. and healthy controls (Berger et al., 1989; Lauer et al., 1988; Gann et al.. 1992; Riemann & Berger, 1989, 1992). The present paper extends the scope of our previous work to include a new group of patients with MDD and a sample of patients with schizophrenia. a psychopathological group which up to now has not been subjected to a cholinergic challenge paradigm (apart from a preliminary report on 11 subjects in each group; Riemann et al.. 1991). A detailed analysis of the results of the chohnergic REM induction test (CRIT) with RS 86 in schizophrenia will be presented, including a differential analysis concerning possible confounding variables and subgroups of schizophrenia. Methods

1. Hecrltll~~cwztds (HC). Thirty-six subjects with a mean age i SD of 4 I .Xk 15.6 years (range: 18-65 years) were studied. Fifteen of the subjects were male, 21 were female. Prior to the investigation all control subjects were carefully screened for organic or psychiatric disorders. To rule out organic disorders results of routine blood tests, a thorough physical examination and an ECG had to be within normal limits. The data for this group have already been reported in detail elsewhere (Riemann et al., 1988). 2. Potirrzts \vithmqjor dcprcxriw dim&r (MDD). Forty inpatients with a major depressive disorder and a mean age of 42.7 k 12.1 years (range: 18-62 years) were studied. Fourteen of the patients were male, 26 were female. Psychiatric diagnoses were made by means of a structured clinical interview (SCID; German version: Wittchen et al.. 1987) according to DSM-III-R (APA. 1987; German version: Wittchen et al., 1989) administered by trained interviewers. Twenty-four patients suffered from depression of the melancholic subtype and 16 from non-melancholic depression. Melancholic and non-melancholic patients did not differ with respect to age, sex or number of episodes of the illness. Thirty-four of the patients suffered from unipolar depression. six patients were either bipolar I or II. All of the subjects fulfilled the RDC-criteria for primary major depression (Spitzer et al.. 1977). Only those patients who were in good physical health (results of a physical examination, routine blood tests. ECG, EEG and CCT-scan had to be within normal limits) were included. For inclusion in the study, patients were required to score > 18 points on the 2 I-item version

SL~J

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of the Hamilton depression scale (21-HAMD) (meanf SD = 26.2A4.9 points; range; 1% 37 points). Mean number of depressive episodes in the sample was 4.5 +6.7 (range: l-30). Mean duration of the current episode was 36.5 f 75.5 weeks (range: 2-416 weeks). All the patients were drug-free for at least 7 days prior to the investigation. None of the depressed patients had received fluoxetine or depot neuroleptics prior to the study. 3. Patients rraithsclkophrenia (SCHIZ). Forty-three inpatients with a mean age of 29.3 + 6.7 years (range: 19-49 years) were studied. Thirty of the patients were male and 13 were female. Diagnoses were also made using the structured clinical interview according to DSM-III-R. According to these criteria. 10 patients qualified for paranoid schizophrenia, five fell into the category of the schizophreniform subtype, 21 suffered from the residual type of the disorder and seven patients fell into the category of undifferentiated/disorganized schizophrenia. These subgroups did not differ with respect to age or sex. With regard to the prior course of illness. five patients suffered from acute schizophrenia, 12 patients were subchronic and the remainder were chronic. Mean duration of illness in the whole sample was 4.7 _t 5.0 years (range: 0.1-26 years), mean duration of the current episode of the illness was 141.7+ 199.4 weeks (range: IL1000 weeks). Negative symptoms as measured by the SANS (Scale for the Assessment of Negative Symptoms; Andreasen, 1983) in the whole sample averaged I I .4+_4.9 points (range: O-20 points; n = 39, four missing values). When applying RDC-criteria for secondary depression. 10 patients qualified for a secondary major depression. Mean 21-HAMD (&SD) in the whole sample was 15.7 + 9.1 points (range: 2238 points; II = 41, two missing values). With regard to family history data (i.e. psychiatric illnesses in first-degree relatives) information was collected from patients, relatives (using the SCID) and case records. Seven patients, for whom no reliable information could be gathered, were discarded from this analysis. Of the remaining subjects, 20 patients did not not have any relative with any psychiatric disorder. Six patients had a first-degree relative exclusively with a depressive disorder and 10 patients had at least one first-degree relative with some other psychiatric disorder (mostly alcoholism, no depressive or manic disturbances). The same criteria of physical health were applied as for the depressed patients. All patients were drug-free for at least 7 days prior to the first night in the sleep laboratory. Twenty-four patients were drug-free for 7-14 days, nine patients had been off medication for at least 14 days and 10 patients had never received psychoactive medication prior to the study. The patients who received depot neuroleptics prior the study (n = 4) had had their last injection at least 28 days prior to the start of the sleep laboratory investigations. The study was approved by the local ethical committee. Prior to participation in the study. all control subjects and patients were informed in detail about the study and gave their written informed consent. All participants has been informed that they could withdraw from the study at any time.

Healthy subjects and patients slept 4 nights in the sleep laboratory. The first 2 nights served for adaptation. Prior to nights 3 and 4, placebo or 1.5 mg RS 86 was given at 22.00

198

D. RIEMANN et al

in a randomized double-blind cross:over design. In a previous investigation 1989) no carry-over effects of RS 86 in the following night were detected, experimental procedure in the present study.

(Berger et al., justifying our

Sleep recordings were performed by a 17 channel Nihon Kohden EEG polysomnograph from “lights out” (23.00f 30 minutes) to ‘-lights on” (07.00) at a paper speed of 10 mm/set. Sleep recordings registered EEG (C3-A2; C4-A I), horizontal EOG and submental EMG. The following filter settings were used: EEG: sensitivity 7 pV/mm. time constant (TC) 0.3 sec., high frequency filter (HI) 70 Hz.; EOG: sensitivity 30 pV:!mm, TC 1.O sec., HI 35 Hz.; EMG: sensitivity 5 /IV/mm. TC 0.03 sec., HI 500 Hz. All subjects (patients and volunteers) were asked to refrain from napping throughout the study protocol; however, no EEGmonitoring was performed during the day to control for day-time napping. Thirty-second epochs of sleep recordings were scored blind to diagnosis and experimental condition by experienced raters according to standardized criteria (Rechtschaffen & Kales, 1968). Interrater reliability for sleep EEG recordings in our laboratory is checked bimonthly. Coefficients of agreement (Kappa) vary between 0.80 and 0.90. Sleep recordings were evaluated for parameters of sleep continuity and architecture. and REM sleep. Sleep continuity variables included: (I) sleep efficiency: ratio of total sleep time (TST) to time in bed (TIB) x 100%; (2) sleep latency: time from lights out till sleep onset (first epoch of stage 2); (3) number of awakenings: at least one epoch of stage wake during sleep period time (SPT = time from sleep onset till the final awakening during the record); (4) early morning awakening: time from the last epoch of stage 2. 3. 4 or REM during the record till lights on. Sleep architecture variables included: amounts of stages wake, 1, 2, SWS (i.e. slow wave sleep, stages 3 and 4 combined) and REM expressed as percentage of SPT. REM sleep variables were: (I) REM latency: time from sleep onset till the first epoch of REM sleep; (2) duration of the first REM period in minutes; (3) eye movement density of the first REM period in %; (4) total REM density. i.e. eye movement density of all REM periods taken together in % (REM density is defined as the ratio of 3 seconds mini-epochs per REM period including at least one rapid eye movement to the total number of 3 seconds miniepochs per REM sleep x 100%).

RS 86, a spiropiperidyl derivative, is a direct muscarinic agonist. Due to its minor side effects, no peripheral antidote has to be applied. RS 86 passes the blood--brain barrier and has a half-life of 6-8 hours (for pharmacology, see Palacios et al., 1986). Recent pharmacological evidence (Stall & Miiller, 1991) indicated that RS 86 is a mixed Ml/M2 receptor agonist with only a slight preference for the M 1 receptor. Stnlistics

For descriptive purposes, mean i SD were calculated. For inferential statistics, analysis of covariance (ANCOVA) was performed with the factors repeated measurements (placebo vs RS 86 = treatment), group (healthy controls, MDD, schizophrenia), interaction (treat-

SLEEP

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ment x group) and age as covariate. Statistical contrasts were calculated for significant ANCOVAs (p < .05). In the case of multiple comparisons, the alpha-level was adjusted according to the Bonferroni method. The level of significance was set at 5% (two-tailed). For statistics, the SAS programme (1985) was used.

Results Impuct

qf RS 86 on sleep. Comparison qf the three incestigated groups

The three groups differed significantly in age (ANOVA, p < .OOl); while the age distribution of healthy controls and patients with MDD was similar, patients suffering from schizophrenia were significantly younger than the other two groups (vs depressed patients, p < .OOl; and vs healthy controls, p < .OOl). There was also a significant gender difference among the three groups (Chi-square test, p < .Ol), with a preponderance of male patients in the group with schizophrenia. Age, but not gender, is known to affect the relevant dependent measures. In order to control for the observed age difference, an ANCOVA with age as a covariate was calculated with the factors being repeated measurement (placebo vs RS 86) and group (healthy controls, primary MDD, schizophrenia). Tables la and b depict the sleep data of the three groups and the results of the statistical analysis. As can be seen, aye had a strong impact on many of the investigated variables. Sleep efficiency, number of awakenings, early morning awakening, stages wake and l%SPT, slow wave sleep %SPT, REM latency and the duration of the first REM period showed significant age effects. As regards the treutment factor (placebo vs RS 86) a significant effect was observed for SWS %SPT and an almost significant effect (p < .lO) occurred for REM

Healthy controls (n = 36) Placebo RS 86 Sleep continuity Sleep efficiency % Sleep latency min No. awakenings Early morning awakening min

Primary M DD (n = 40) Placebo RS 86

Schizophrenic disorders (II = 43) Placebo RS 86

88.4*8.2 20.6k17.4 8.4k5.5 5.5* 13.7

w2+7.5 19.6ill.9 9.1 +5.6 3.5k9.8

82.li 13.2 22.4i 15.0 16.6i 14.0 16.6i25.4

80.8& 13.7 30.5k22.3 19.6+ 15.6 8.4i 13.1

80.5 i 14.4 45.5k47.6 lO.5k6.8 15.8k32.5

80.8& 13.9 54.7 + 65.4 9.4k7.4 12.8+21.6

Sleep architecture Stage wake %SP stage I %“SP stage 2 %SP stage sws %SP Stage REM %SP

6.0 i 6.2 8.2k5.l 56.Oi7.9 10.6k9.7 18.4k4.0

6.8k5.4 7.6k4.3 56.Ok9.1 7.2+&O 22.0 f 5.x

10.3i_ 12.1 10.3k6.1 50.7+ Il.5 5.7k7.2 22.4 k 7.4

I l.8+ 12.7 ll.7k6.7 45.9* 12.0 3.4i4.9 26.6 + 8.7

6.6 f 8.3 8.3k6.l 49.5 f 10.3 ll.6*8.0 22.9 f 5.6

5.6k6.3 9.5 * 7.4 49.7 f9.6 7.2 f 6.2 27.3 + 7.3

REM-sleep REM latency min I. REMP duration min I. REM density % Total REM density %

72.4k25.7 16.8+ 12.0 21.9* IO.5 28.2? 10.9

55.5 f 20.7* 24.2* 27.0f

48.2k27.4 29.Oi_ 18.8 25.3+ 12.2 27.6, 10.0

19.8k20.4 31.7i23.3 30.6i 15.5 28.9k9.3

66.9k40.7 l9.2i 14.4 15.Ok8.4 21.2i7.5

38.5 + 52. I 21.3* 18.9 17.7* 13.3 21.357.6

36.5 16.0 10.7 10.9

200

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latency. When taking a closer look at REM latency data, it became obvious that delta REM latency (the difference in REM latency between placebo and RS 86) was significantly negatively correlated with age in MDD (,- = -0.40; p < .Ol) but not in HC (Y = 0.18; ns) and schizophrenia (Y = 0.14; ns). Due to this discrepancy, a second ANOVA was calculated without age as a covariate, which yielded a highly significant treatment effect (p < ,001). In comparing the diugnosis factor in the three groups, significant effects were noted for all sleep variables investigated. For none of the variables under investigation were any significant interaction effects (treatment x group) observed. The next step of the analysis included calculation of contrasts for the diagnosis factor, comparing HC to MDD and schizophrenia, and patients with schizophrenia to patients with MDD. Maintenance of the overall alpha-level at 5% required a p-value of .016 for these multiple comparisons (see underlined p-values in Table 1b).

HC z’s MDD. Healthy controls showed a higher sleep efficiency and a reduced number of awakenings compared to MDD patients, who in turn showed heightened percentages of stage awake, Stage 1 and REM sleep (%SPT) but decreased amounts of Stage 2 and SWS (%SPT) compared to HC. REM latency in MDD was shortened and the duration of the first REM period prolonged. The density of the first REM period tended to be enhanced in patients with MDD.

HC 1’s schizopphreniu. Fewer differences were noted between HC and patients with schizophrenia. The latter showed a lower sleep efficiency, prolonged sleep latency and a more marked early morning awakening. Stage 2 and slow wave sleep (%SPT) were reduced and REM sleep (%SPT) was enhanced in patients. Total REM density was reduced in comparison to healthy controls.

MDD z’s sc~hi~ophrenia. Patients with schizophrenia had lower sleep efficiency and prolonged sleep latency. REM latency tended to be shorter in depressives than in schizophrenia whereas both parameters of REM density were decreased in schizophrenia compared to MDD. Figure 1 shows single values of REM latency for placebo and 1.5 mg RS 86 for all groups investigated. It can be seen that at a REM latency threshold of 25 minutes (see our previous work, Berger et al., 1989). six of the HC (16.7%) displayed such a drastic shortening of REM latency after cholinergic stimulation. Seven of the patients with MDD (17.5%) already fell below this threshold under placebo conditions and cholinergic stimulation raised the incidence of very short REM latencies in this patient group to n = 25 (62.5%). Five patients with schizophrenia (11.6%) displayed a REM latency < 25 minutes under placebo as did 19 others (44.2%) after RS 86. The effect of a McNemar test for the occurrence of REM latencies < 25 minutes was significant (p < .OOOl) when comparing placebo and RS 86 conditions. Contrasting the three groups for the occurrence of REM latencies 625 minutes after RS 86 (Chi-square test), patients with MDD and patients with schizophrenia both differed from HC (p < ,001 and p < .Ol). but not from each other.

202

D. RIEMANN et al PRIMARY

HEALTHY

MCIU

CONTROLS mm

n=LO

n=36

n = 43;,’

296.0

200 -

0 Plac

RS86

Plac

RS86

Plac

RS86

Fipm 1. Impact of 1.5 tng RS 86 on REM latency in comparkon to placebo (Plac) in 36 healthy controls. 40 patients with primary MDD and 43 patients with schizophremc disorders. Dashed line: REM latency threshold of 25 minutes. Arrows mark medlana.

Analysis qf’confounding

cariables in the group @patients

with schizophrenia

Depressive .~yn~ptornatolog~~~~~rnil~history. The incidence of REM latencies < 25 minutes after cholinergic stimulation did not differ between schizophrenic patients with or without secondary depression: five (50%) of the patients with a secondary MDD and 14 (42.4%) of the 33 patients without a secondary MDD displayed such a distinct shortening of REM latency following cholinergic challenge. The results of a correlative analysis (relating severity of depression as measured by the 21-HAMD to REM sleep variables) are shown in Table 2. For the placebo condition correlation of both measures of REM density with severity of depression was significantly negative. None of the REM sleep measures after cholinergic challenge showed a significant correlation with the 21-HAMD. For delta values with the 21-HAMD (placebo-RS 86) as well, correlation of both measures of REM density was significantly negative. Next, the impact of a positive family history of depressive disorders on the results of the CRIT was analyzed. Unfortunately, no such information was available for seven of the 43

SLEEP IN SCHIZOPHRENIA

203

Table 2 Secrritv qf depression (21.HAMD) coqfficrknts(age partialled out /

and REM sleep measures in .schi:ophrenicpntirnts

Placebo Variable REM latency min 1. REM period duration I. REM density % Total REM density % REM % SPT

min

*n = 2 subjects did not have a 2l-HAMD

(n = 41*); product-moment

(Placebo-RS

RS 86

86)

r

P

r

P

r

P

.09 -.I5 -.55 -.37 -.Ol

.5787 .333l .0002 .Ol90 .9286

~ .05 .I0 .24 .I6 -.19

.7642 ,521 I .I431 .3216 .2413

.I2 -.I9 - .50 - .38 .I6

.4637 .2423 .0009 .0155 .3146

rating.

patients, mandating restriction of this analysis to 36 patients. In the group of patients without a positive family history of any psychiatric disorder (n = 20) nine REM latencies 625 minutes after cholinergic stimulation occurred. In the six patients who had a firstdegree relative with major depression three shortened REM latencies and in the 10 patients who had a first-degree relative with another psychiatric disturbance five REM latencies ~25 minutes were observed. ANCOVA did not reveal any significant difference between the three groups with regard to REM latency or any other REM sleep variables after placebo, RS 86 or for delta values (data not shown). SubtJlpes qf schizophrenia/course of the disorder/negative symptoms. The statistical analysis (ANCOVA) did not reveal any difference between schizophreniform, paranoid, residual and undifferentiated/disorganized schizophrenia with regard to REM latency or any other parameter of REM sleep (data not shown). Furthermore, the impact of the course of the disorder (acute, subchronic, chronic) on the CRIT was analyzed. REM latency and other REM sleep variables did not discriminate between the three groups (data not shown). Additionally, correlations of REM sleep variables with negative symptoms (as measured by the SANS) were calculated. Only two coefficients did reach the level of significance of p < .05 when correlating REM measures during placebo with the SANS general score. Total REM density (r = - 0.34) and density of the first REM period (r = -0.35) correlated negatively with the SANS sum of global scores score (p < .05). Length qfdrug brash-out interaal. Twenty-four patients had been off medication for 7-14 days, nine had received no psychoactive medication for at least 15 days and 10 patients had never before taken any kind of psychoactive drug. Statistical analysis (not shown) did not reveal any significant difference between the groups. It is interesting to note that mean REM latency after cholinergic stimulation was lower (though not statistically significant) in the psychotropic-naive group (mean f SD = 15.7 f 24.3 minutes) in comparison to the group of patients medication-free for only 7714 days (mean = 45.6 f 59.4 minutes).

Discussion l$kts

of age and RS 86 on sleep and group d$fi’rence.s

Age effects on sleep observed in the present dataset are in line with previous investigations on the relationship of age and sleep in healthy subjects and patients with depression (Gillin

204

D. RIEMANNet al.

et al., 1981; Lauer et al., 1991). To control for the significant age difference between the schizophrenic sample and the two other groups, age was treated as a covariate in the data analysis. With regard to the impact of RS 86 on sleep parameters, a significant reduction of SWS (%SPT) and a highly significant shortening of REM latency was noted. The shortening of REM latency and reduction of SWS observed confirms findings from earlier studies with the cholinergic REM induction test (see for example Berger et al., 1989; Gillin et al., 1991). Our data in depressed patients are consistent with the tenets of the reciprocal interaction model of non-REM-REM sleep regulation (Hobson et al., 1975, 1986) and its implications for affective disorders (McCarley, 1982). According to this model, REM sleep is triggered by cholinergic neurons located mainly in the brainstem, which are closely connected with cholinergic neuronal networks in higher brain areas. Furthermore. it is assumed that the early onset of REM sleep observed in MDD under baseline conditions and after cholinergic stimulation reflects an imbalance between central nervous aminergic and cholinergic transmitter systems with a relative overactivity or a supersensitivity of muscarinic receptors. Fast REM induction response in MDD may be further interpreted as supportive of the cholinergic--aminergic imbalance model of affective disorders (Janowsky et al., 1972; Janowsky & Risch, 1986). Evidence from animal experiments suggests that besides an induction of REM sleep, cholinergic mechanisms are implied in the blockade of slow waves (Buzsaki et al., 1988; Steriade et al., 1991). which may explain the simultaneous reduction of REM latency and slow wave sleep seen in the present investigation. Expected differences between healthy controls and patients with MDD were observed (see for example Reynolds & Kupfer, 1987); patients with MDD exhibited disturbed sleep continuity, reduced SWS and abnormalities of REM sleep. Fewer differences were noted when comparing patients with schizophrenia and healthy subjects. The former group showed, compared to depressed patients. a significantly impaired sleep efficiency, longer sleep latency and lower REM density. With respect to REM latency. the schizophrenic group to an impressive degree also displayed very short REM latencies both under placebo and after cholinergic stimulation. Nineteen of 43 schizophrenic patients (44%) had REM latencies <25 minutes after cholinergic challenge. These results clearly demonstrate that the REM latency of patients with schizophrenia is almost as hyperresponsive to cholinergic challenge as is that in patients with a primary MDD. Interestingly. in contrast to REM latency, REM density more clearly differentiated between MDD and schizophrenia. These data further support the contention that REM density measures may be better markers of depressed sleep (Lauer et al., 1991; Keshavan & Tandon, 1993; Riemann et al., 1994); the combination of shortened REM latency N& simultaneous increase of REM density seems to be more specific for depression than reduced REM latency alone. Co~~fOunthg

writrhlrs

in mtrlj~sis

of’slct~p

rcrrit~h1r.s irl .~t,hi~ol)hrrrzicr~~~it~

Before interpreting data of the schizophrenic ables have to be discussed. Deprrssion.

Keshavan

et al. (1990) speculated

sample. several possible confounding

that the presence

and severity

vari-

of a sec-

SLEEP IN SCHIZOPHKEUIA

205

ondary MDD in schizophrenia may explain depression-like sleep abnormalities in this patient group. When splitting our sample of patients with schizophrenia into those with and without a secondary depression. no difference emerged concerning sleep parameters. Also, a family history for depressive/manic disorders did not contribute to shortened REM latency in the group of patients with schizophrenia. Interpreting our data conservatively (acknowledging the reduced statistical power due to small sample sizes when comparing subgroups of schizophrenia and the limitations of our approach to collect family history data), it seems reasonable to state that neither the presence and degree of depressive symptoms nor a family history for depressive/manic disorders can be held solely responsible for shortened REM latencies observed in this group. Subtl,pes qf schi~ophrrnialcoursp of’ the r~i.~or~erllzeyati~e symptoms. In an earlier study it was found that patients with acute schizophrenia did not display REM sleep abnormalities (Ganguli et al., 1987) whereas for chronic/residual patients shortened REM latency was described (e.g. Jus et al., 1973; Hiatt et al., 1985; Kempenaers et al., 1988; Kumar et al., 1985; Maggini et al., 1986; Tandon et al., 1988; Zarcone et al., 1987). Our data indicate that a pronounced induction of REM sleep in the CRIT is not linked to a specific subtype of the disorder or a chronic course. It should be noted that our subgroup of acute patients was rather small (only five patients), therefore requiring replication of our data in a larger sample. Tandon and co-authors (1988) observed that a combined index of REM latency and REM density correlated with negative symptoms as measured by the SANS. The same group was able to replicate the relationship between negative symptoms and shortened REM latency (Taylor et al.. 1991) although Tandon et al. (1992) only found an inverse relationship between REM latency and negative symptoms in patients with prior treatment but not in drug-naive patients. Ganguli et al. (1987) also were unable to detect such a relationship in young drug-naive patients. Measures of REM density, but not REM latency, in the present dataset during placebo correlated significantly negatively with the SANS score thus at least partially replicating data of Tandon and co-workers. Drug wash-out. Twenty-four patients in our investigation had been off psychoactive medication prior to the study for only 7714 days. Other reports described that after withdrawal of neuroleptics the sleep EEG undergoes changes which may not return to baseline values within 7 days (Thaker et al., 1989, 1990; Tandon et al., 1992). Thaker and co-workers (I 989, 1990) found that neuroleptic withdrawal in schizophrenic patients who were concomitantly treated with anticholinergics led to a suppression of REM sleep. In contrast, Tandon et al. (1992) described shorter REM latencies in patients previously treated with neuroleptics compared to drug-naive patients. Interestingly, in our dataset those patients never having received psychoactive medication were those with the shortest mean REM latency after cholinergic stimulation. Mean REM latency under placebo conditions did not differ between the three groups. Also, none of the other REM sleep parameters in the present study covaried with the length of the drug wash-out interval. Therefore it seems unlikely that sleep data of schizophrenic patients in the present study were strongly influenced by withdrawal from neuroleptics. This result is in line with a study

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D. RIEMANN et al

by Lauer and Pollmacher (1992) who demonstrated that visually scored sleep in patients with depression was not dependent on the length of the prior wash-out interval (if at least 7 days of drug wash-out were followed). E.xplanations,fbr

the shortening ?f’REM

latency> in schizophrenia

The (17olirlergi~lnzus~arini~ IIypothesis. Tandon and Greden (1989) in analogy to models of depressed sleep (Sitaram et al., 1979; Gillin et al., 1979) suggested that REM sleep abnormalities in schizophrenia should be interpreted as a consequence of a supersensitivity of muscarinic receptors. Furthermore the authors assumed that in chronic schizophrenia an increase of cholinergic activity might serve as an adaptive counterregulatory mechanism to compensate for increased dopaminergic activity, which has been implicated in the pathophysiology of schizophrenia (for an overview of the dopamine hypothesis of schizophrenia see Carlsson, 1988). Tandon and Greden (1989) additionally assumed that the typical symptoms of chronic/residual schizophrenia might be due to heightened cholinergic drive. This line of reasoning was based on pharmacological studies with cholinomimetics which demonstrated increased anhedonia, avolition, apathy and hypoactivity after physostigmine stimulation in healthy subjects (Tandon et al., 1993). In favor of the muscarinic hypothesis of schizophrenia are studies with anticholinergics; Tandon et al., (1990. 1991) demonstrated that treatment with biperiden. a preferential M 1-receptor antagonist, reduced negative symptoms and increased positive symptoms in schizophrenia. Furthermore REM sleep suppression following biperiden was less marked in schizophrenia than in healthy controls. The postulated relationship between cholinergic mechanisms, REM sleep abnormalities and schizophrenia is further supported by a study describing a significant negative correlation between plasma cholinesterase isozyme activity and REM latency in schizophrenia (Keshavan et al., 1992). However, a recent study analyzing post-mortem brain tissue from the pontine tegmentum in this patient group (Karson et al., 1993) found lower concentrations ofcholine acetyltransferase in schizophrenics than in healthy subjects. which the authors interpreted as evidence for a reduced cholinergic activity in schizophrenia. So far. beyond the sleep data, the picture concerning the involvement of cholinergic mechanisms in the etiology of schizophrenia is far from being clear. DoparCwrgic mechanisms. A dopaminergic influence on non-REM-REM regulation has been mostly neglected in models of sleep regulation. Sternberg & Porkka-Heiskanen (1990) postulated a modulatory impact of dopaminergic neurotransmission on REM sleep. They showed that bromocriptine. a dopamine (D-2) agonist, reduced REM sleep, whereas the D-2 receptor antagonist sulpiride did not influence REM sleep in cats. These authors concluded that dopaminergic neurotransmission does not have a direct influence on REM sleep regulating mechanisms, but primarily exerts an influence on hypnogenic factors, which in turn. interact with REM sleep. Extrapolating from the dopamine hypothesis of schizophrenia (see Carlsson, 1988) one would expect normal or reduced REM sleep in schizophrenia. Our findings of a reduced REM latency in a subgroup of patients with this disorder needs to take into account muscarinic mechanisms which counteract a heightened dopaminergic input.

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Reduced REM density in schizophrenia Perhaps as significant as our finding of reduced REM latency in schizophrenia is our observation of reduced REM density in schizophrenic patients in comparison to MDD and healthy subjects. Tandon et al. (1992) summarizing the relevant literature, found heightened REM density in schizophrenia in only one study (Gulevich et al., 1967) which, however, utilized only a 4-day drug wash-out. Tandon et al. (1992) themselves found increased REM density only in previously neuroleptic-treated schizophrenics but not in drug-naive patients. Other studies in the field did not find any differences in REM density between healthy subjects and schizophrenics. In view of the above-mentioned results it seems unlikely that reduced REM density in the present study in schizophrenia was due to insufficient drug wash-out. Several models may serve to explain changes in REM density. Aserinsky (1969, 1973) observed that REM density is related to “sleep satiety”, i.e. the amount of an individual’s prior sleep. According to this model, REM density increases across the night due to the simultaneous increase of sleep length. As patients with schizophrenia in our study displayed the most disturbed indices of sleep continuity (reduced sleep efficiency, prolonged sleep latency), our data are compatible with the assumption that reduced sleep satiety leads to decreased REM density. This hypothesis fits well with the postulated impact of dopaminergic neurotransmission (which is assumed to be enhanced in schizophrenia, see for example Carlsson, 1988) on hypnogenic factors. Sternberg and Porka-Heiskanen ( 1990) postulated that dopamine inhibits hypnogenic factors and thereby leads to insomnia. It is, however, difficult to interpret the well-known phenomenon of an increased REM density in depressed patients (see for example Reynolds & Kupfer, 1987) who do not sleep much better than schizophrenics, within this context. Conclusions These data confirm previous findings of short REM latency in schizophrenia and major depressive disorder and strongly indicate a role for muscarinic cholinergic supersensitivity in the production of this abnormality in both these disorders. REM density measures. but not REM latency, differentiated patients with MDD from those with schizophrenia. The finding of short REM latency in schizophrenia was not due to a latent affective diathesis. but appeared to be intrinsic to the schizophrenic disorder. While muscarinic supersensitivity occurs in both schizophrenia and MDD, the precise relevance of this abnormality in these disorders is unclear. Ackno~~/~,~/gen?ents-This research was supported by a grant from the DFG Nuding and Martina Schnitaler for excellent secretarial assistance In preparing

(SFB 258, Al). this manuscript.

We thank

Edith

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