Theme : Dreams
Sleep and the Cholinergic REM Sleep Induction Test in Patients with
Primary Alcoholism
Horst Gann, Anke Faulmann, Andrea Kiemen, Thorsten Klein, Dieter Ebert,
Jutta Backhaus, Magda Hornyak, Uli Voderholzer, Fritz Hohagen, Mathias
Berger and Dieter Riemann
Department of Psychiatry and Psychotherapy, University of Freiburg, Freiburg,
D-79104, Germany
Abstract
Sleep disturbances of alcoholics while actively drinking and at the beginning
of, and during, abstinence were frequently reported. Recently, Gillin
et al. (1994) showed that a high "REM sleep pressure" at the
time of admission to a 1-month inpatient alcohol treatment program predicted
the relapse in nondepressed patients with primary alcoholism at 3 months
following hospital discharge. We investigated 24 patients with primary
alcoholism after 2-3 weeks abstinence in the sleep laboratory; in 15 of
these patients the cholinergic REM sleep induction test (CRIT) with 10
mg galanthamine was performed additionally. In comparison with an age-
and sex-matched healthy control group, patients had a heightened "REM
sleep pressure" including shortened REM latency and increased REM
density. A decrease of serotonergic neurotransmission is proposed as being
the neurochemical mechanism to explain the results in alcoholic subjects.
Follow-up investigations will clarify whether the sleep abnormalities
in alcoholism are state- or trait-markers and whether they are suitable
to predict the relapse risk.
Current Claim: Alcoholic patients at the beginning of abstinence have
significant sleep continuity and sleep architecture disturbances.
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Alcoholic patients often complain of sleep disturbances during periods
of drinking, but also during acute withdrawal, as well as during subacute
and chronic abstinence (Gross and Hastey, 1976). Recovered alcoholic patients
may show persistent sleep abnormalities for months and years (Wagman and
Allen, 1975). Such sleep abnormalities are reduced total sleep time, loss
of delta sleep, poor sleep efficiency and REM (Rapid Eye Movement) sleep
abnormalities.
Recently, Gillin et al. (1994) showed that short REM latency, increased
REM percentage and, possibly, increased REM density at the time of admission
to a 1-month inpatient alcohol treatment program predicted the relapse
in nondepressed patients with primary alcoholism at 3 months following
hospital discharge.
To extend the investigations of Gillin et al., and to clarify possible
neurochemical mechanisms underlying increased "REM pressure,"
we examined the influence of the cholinesterase inhibitor galanthamine
hydrobromide on the sleep of patients with primary alcoholism at the beginning
of their abstinence. In an earlier study (Riemann et al., 1994) we were
able to show that 10 mg galanthamine shortened REM latency and increased
REM density in healthy subjects.
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Subjects
The subjects consisted of 24 patients with primary alcoholism (see Table
1) and two control groups: a) n = 24, age- and gender-matched subjects
for baseline comparisons and b) n = 15, age- and gender-matched subjects
for CRIT. The control group b) includes data of subjects published earlier
(Riemann et al., 1994). The patients had been admitted for treatment of
alcoholism to our department, which offers a 21-day inpatient treatment
program. Patients were invited to participate in a multidisciplinary,
longitudinal investigation. As part of this ongoing study, subjects were
asked to participate for three consecutive nights of polygraphically recorded
sleep during the third week of hospitalization, and at 6- and 12-month
follow-ups after discharge.
All subjects underwent a full medical and psychiatric investigation and
physical examination: routine clinical and hematologic laboratory examinations,
urinalyses, ECG, EEG and MRI. All patients met the criteria for alcoholism,
using DSM-III-R criteria (diagnosis was made with the Structured Clinical
Interview, SCID, German Version [Wittchen et al., 1988]). Primary alcoholism
refers to patients without another psychiatric illness or significant
medical problem prior to the onset of alcoholism.
We excluded patients with psychosis, clinically significant cognitive
impairment, antisocial personality, substance abuse and major medical
problems (for example, cirrhosis of the liver). Patients with secondary
MDD or dysthymia were not excluded. All patients were free of any kind
of psychoactive medication for a minimum of 7 days prior to the investigation.
The study had been approved by the local ethical committee and each patient
signed written informed consent prior to inclusion.
Drug
Galanthamine hydrobromide, an alkaloid isolated from the snowdrop galanthus
nivalis, is a reversible and selective inhibitor of acetylcholinesterase.
Maximal plasma concentrations of the drug are reached 2 hours after oral
ingestion. The elimination half-life time is 5.3 (SD = 4.2) hours (for
detailed information, see Riemann et al., 1994).
Design
Subjects slept in the sleep laboratory for three nights, with the first
night serving to adapt them to the laboratory. In the first night, subjects
were screened for sleep apnea and periodic movements of sleep (PMS); exclusion
criteria were an apnea-hypopnea index greater than 10/h and a PMS-Index
greater than 15/h. We administered at 9 p.m., before nights 2 and 3, a
single oral dose of 10 mg galanthamine or placebo (= baseline night) in
a double-blind randomized cross-over design. Patients with contraindications
against cholinergic drugs received the placebo twice.
Sleep
Sleep was registered between "lights out" (23:00) and "lights
on" (07:00) using standard procedures (EEG: C 4-1; C 3-A2; horizontal
EOG, submental EMG). Records were scored by raters blind to experimental
conditions according to standardized criteria (Rechtschaffen and Kales,
1968). Polysomnograms were then evaluated for parameters of sleep continuity,
architecture and REM sleep. REM latencies were evaluated as time from
sleep onset (first epoch stage 2), to the first epoch of stage REM (=
REM latency 1), and time from sleep onset (10 min continuous stage 2 interrupted
only for 1 min of either stage wake or stage 1), to the first epoch of
three consecutive minutes of REM sleep minus intermittent wake time (=
REM latency 2). For a detailed description of the algorithms in our laboratory,
see Riemann et al. (1994).
Statistics
Descriptive statistical parameters include presentation of mean and standard
deviation. For group comparisons (baseline data) the two-tailed t-test
was used. For the CRIT repeated measures analysis of variance (ANOVA),
corrected according to the method of Greenhouse and Geisser, was used.
Only for significant ANOVAs were contrasts calculated.
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Baseline data
Data from 24 patients without cholinergic stimulation were compared with
24 age- and sex-matched controls (see Table 2). Patients showed significant
sleep continuity disturbances (lowered sleep efficiency, heightened number
of awakenings, heightened time awake) and sleep architecture disturbances
(decreased slow wave sleep [SWS]). Furthermore, patients displayed an
increased "REM sleep pressure" with heightened total REM density,
heightened density of the 1 REM period and decreased REM latency (definition
2).
Cholinergic REM induction test (CRIT)
The CRIT was applied in 15 patients. No side effects of galanthamine
were observed. Side effects in control subjects are described in detail
elsewhere (Riemann et al., 1994) and included mild hypersalivation, mild
hyperhydrosis and slightly disturbed sleep. Table 3 summarizes the results
concerning sleep variables of the two groups for placebo and galanthamine
conditions. Significant effects of the groups were noted for time awake,
SWS (%SPT), REM period 1 density and total REM density. Significant effects
of treatment were observed for S2-latency, time awake (%SPT), stage 1
(%SPT), stage 2 (%SPT), SWS (%SPT), REM period 1 duration and REM period
1 density.
Calculation of contrasts within controls and patients for treatment effects
revealed the following results: While in controls, galanthamine led to
significant sleep continuity disturbances (heightened sleep latency and
heightened time awake) and sleep architecture disturbances (reduced SWS),
no such effect occurred in the patients. The REM sleep-inducing effect
of galanthamine was stronger in controls (see p-value for REM period 1
duration and density) while in controls REM latency 2 was reduced from
69.6 min (placebo) to 50.9 min (galanthamine). In the patients there was
even a lengthening of REM latency with the CRIT. The difference was, however,
not statistically significant.
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in this area and automatically retrieved upon your next visit.
Alcoholic patients at the beginning of abstinence had significant sleep
continuity and sleep architecture disturbances; "REM sleep pressure"
was heightened in the patients. The cholinergic REM sleep-induction effect
was significantly more pronounced in the controls.
Of the possible neurochemical mechanisms underlying increased "REM
pressure" at the beginning of abstinence, one explanation could be
impaired serotonergic neurotransmission (Le Marquand et al., 1994). The
reciprocal interaction model of the regulation of normal REM sleep implicates
cholinergic promoting and aminergic inhibition of REM sleep (Hobson et
al., 1986). A relative deficiency of serotonergic neurotransmission in
patients with primary alcoholism may be the reason for increased "REM
pressure" as well as for sleep continuity and sleep architecture
disturbances.
Successive polysomnographic investigations (at 6- and 12-month follow-ups)
will clarify whether the sleep abnormalities reflect a persistent withdrawal
syndrome (in the sense of a rebound phenomenon) in recovering alcoholic
patients which would eventually wane, or whether the sleep abnormalities
have a trait-character.
The following catamnestic interviews will further clarify whether the
sleep abnormalities and the CRIT have a predictive value for alcoholic
relapses. Janowsky et al. (1989) found in detoxified patients with primary
alcoholism fewer chances of pulse rate and variables of behaviour after
injection of physostigmine. There is further evidence for impaired cholinergic
neurotransmission in alcoholic patients (Freund and Ballinger, 1988).
Also in the CRIT in our patients we found evidence for a cholinergic sub-sensitivity
at the beginning of abstinence, as patients in comparison to controls
exhibited less REM sleep disinhibition after galanthamine. On the other
hand, minor response to galanthamine also might be explained by a strong
serotonergic system. Alternative explanations for the less pronounced
REM sleep disinhibition after galanthamine in patients are a "ceiling-effect"
(concerning "REM pressure") in the case of a sub-maximum REM
sleep disinhibition already under baseline conditions or alterated liver-metabolism
in patients.
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This research was supported by a grant from the BMBF (01EB9413).
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