Sleep, age, depression and the cholinergic REM induction test with RS 86.

1. Healthy volunteers and patients with a major depressive disorders were administered 1.5 mg RS 86 (a cholinergic agonist) and placebo in a randomized double-blind cross-over design at 10 p.m. prior to bedtime. 2. Polysomnographic recordings demonstrated a significantly more pronounced shortening of REM latency after cholinergic stimulation in depressed patients compared to healthy subjects. 3. Even those depressed patients displaying placebo REM latencies in the normal range showed sleep onset REM periods after cholinergic stimulation. 4. The results support the reciprocal interaction model of NonREM-REM sleep regulation and the cholinergic-aminergic imbalance model of depression.     

Sleep in depression: the influence of age,gender and diagnostic subtype on baseline sleep and the cholinergic REM induction test with RS 86

Summary One hundred and eight healthy controls and 178 patients with a major depressive disorder according to DSM-III were investigated in the sleep laboratory after a 7-day drug wash-out period. Subsamples of 36 healthy controls and 56 patients additionally took part in the cholinergic rapid eye movement (REM) sleep induction test with RS 86. Data analysis revealed that age exerted powerful influences on sleep in control subjects and depressed patients. Sleep efficiency and amount of slow wave sleep (SWS) decreased with age, whereas the number of awakenings, early morning awakening, and amounts of wake time and stage 1 increased with age. REM latency was negatively correlated with age only in the group of patients with a major depression. Statistical analysis revealed group differences for almost all parameters of sleep continuity with disturbed indices in the depressed group. Differences in SWS were not detected. REM latency and REM density were altered in depression compared to healthy subjects. Sex differences existed for the amounts of stage 1 and SWS. The cholinergic REM induction test resulted in a significantly more pronounced induction of REM sleep in depressed patients compared with healthy controls, provoking sleep onset REM periods as well in those depressed patients showing baseline REM latencies in the normal range. Depressed patients with or without melancholia (according to DSM-III) did not differ from each other, either concerning baseline sleep or with respect to the results of the cholinergic REM induction test. The results stress the importance of age when comparing sleep patterns of healthy controls with those of depressed patients. Furthermore they underline the usefulness of the cholinergic REM induction test for differentiating depressed patients from healthy controls and support the reciprocal interaction model of nonREM-REM regulation and the cholinergic-aminergic imbalance hypothesis of affective disorders.     

REM sleep and cortisol response to the cholinergic challenge with RS 86 in normals and depressives

The influence of the muscarinic agonist RS 86 on rapid-eye-movement (REM) sleep and on hypothalamic-pituitary-adrenocortical (HPA) axis was studied in healthy subjects and in patients with a major depression. In both groups, RS 86 induced a shortening of REM latency and an increase in REM sleep; these effects were more pronounced in the depressives than in the controls. This finding supports the assumption that in depression the REM sleep regulating neurons are hypersensitive to cholinergic stimuli. However, neither in the healthy subjects nor in the depressed patients was an RS 86 induced increase in plasma cortisol seen. This observation does not agree with the assumption that, in humans, the HPA axis is stimulated by muscarinic neurons and that hypercortisolemia in depression is due to an overactivity of muscarinic neurons activating the HPA axis.     

REM latency in neurotic and endogenous depression and the cholinergic REM induction test

Latency of rapid eye movement (REM) sleep was measured in eight healthy volunteers under baseline conditions and after administration of physostigmine. An infusion of 0.5 mg of physostigmine 5 minutes after sleep onset caused a significant shortening of REM latency in comparison with baseline conditions. In 45 patients with major depression, REM latency during baseline nights was significantly shorter than in control subjects. This shortening of the REM latency was found to be similar in endogenous, neurotic, and unclassified depressed patients. In contrast to findings in the controls, the physostigmine infusion provoked no further significant reduction of REM latency in depressed patients, but awakened the majority of patients. The data concerning spontaneous REM latency and REM latency after physostigmine do not allow a differentiation among the endogenous, neurotic, and unclassified depressed subgroups. The results of the cholinergic REM induction test do not conclusively support the hypothesis of a cholinergic hypersensitivity in depression.     

The cholinergic agonist RS 86: a pharmacopsychological study

The cholinergic-adrenergic balance hypothesis of affective disorders postulates noradrenergic over-activity and cholinergic hypoactivity in mania and the converse in depression. Some evidence for cholinergic contributions to mood regulation derives from the antimanic and depressiogenic activity of physostigmine and arecoline. However, both drugs have pharmacodynamic and pharmacokinetic disadvantages. Therefore, the orally active muscarinic agonist RS 86 was tested in a double-blind dose-response study for its psychotropic effects in one healthy volunteer. A dose-dependent anergic-anhedonic syndrome was identified in comparison to placebo. The study confirms the physostigmine syndrome to be mediated by muscarinic, possibly M1 receptors, and gives further support to the hypothesis of a cholinergic modulation of mood and behavior in man.     

Cholinergic REM sleep induction test in subjects at high risk for psychiatric disorders.

The influence of the cholinergic agonist RS 86 on electroencephalographic (EEG) sleep was investigated in 21 healthy members of families identified as being at high risk for psychiatric disorders and in 17 healthy control subjects without any personal or family history of a psychiatric illness. In comparison to the placebo night, the administration of RS 86 led to a shortening of rapid eye movement (REM) latency in both groups. This effect, however, was much more pronounced in the high-risk group, whereas in the control subjects the arousal system and the slow-wave sleep during the first nonREM period were more affected. These observations suggest that the cholinergic action on sleep regulating mechanisms has differing preferential targets in high-risk probands and in control subjects.     

The cholinergic rapid eye movement sleep induction test with RS-86. State or trait marker of depression?

Rapid eye movement (REM) sleep disinhibition at the beginning of the night is one of the most frequently described biologic abnormalities in depression. As REM sleep in animals and humans seems to be facilitated by cholinergic neuronal activity, it has been postulated that REM sleep disinhibition in depression is a consequence of cholinergic neuronal overactivity. The current study with the newly available cholinergic agonist RS-86, which is orally active, has a half-life of six to eight hours, and exhibits only minor peripheral side effects, supports this assumption. The application of this compound before sleep led to a significantly faster induction of REM sleep at the beginning of the night in patients with major depressive disorders compared with healthy subjects and patients with other nondepressive psychiatric diseases, such as eating disorders. Whereas 14 of 16 depressed patients displayed sleep-onset REM periods after the administration of RS-86, this happened only in three of the 16 healthy controls and in one of the 20 patients with other diagnoses. The increased susceptibility of REM sleep to cholinergic stimulation was limited to the state of depression and was not observed in a group of remitted depressed patients.     

The cholinergic rapid eye movement induction test with arecoline in depression

The cholinergic rapid eye movement (REM) induction test using arecoline hydrobromide, a cholinergic muscarinic receptor agonist, was studied in patients with affective disorder and in normal controls to determine whether or not depression is associated with enhanced induction of REM sleep by muscarinic agonists. Arecoline induced REM sleep in a dose-dependent fashion in both patients and controls compared with placebo infusions. Compared with normal controls, patients entered REM sleep significantly more rapidly following intravenous administration of 1.0 mg of arecoline hydrobromide than they did following administration of 0.5 mg of arecoline hydrobromide or placebo. These results, as well as those of previous studies, support the hypothesis that patients with affective disorder show a functional supersensitive induction of REM sleep in response to muscarinic receptor agonists and may be consistent with the hypothesis that functional muscarinic receptor "up regulation" is associated with depression.     

The metyrapone test in manic patients and healthy subjects

The metyrapone (Metopiron) test (MT), a useful and reliable procedure for assessing hypothalamic-pituitary-adrenal (HPA) axis function, was applied to manic patients and healthy subjects. Three out of 11 patients had high normal responses to metyrapone, as observed in patients with Cushing's disease. One patient exhibited a subnormal response to metyrapone, as occurs in patients with adrenal insufficiency. No such abnormalities were detected in 11 matched healthy control subjects. These preliminary results suggest that the HPA axis activity patterns in mania may be more complex than previously reported.     

The metyrapone test in schizophrenic patients and healthy subjects

The metyrapone test, a useful and reliable procedure for assessing hypothalamic-pituitary-adrenocortical (HPA) axis function, was applied to schizophrenic patients and healthy controls. 4 out of 18 patients had subnormal responses to metyrapone whereas there were no such cases in the 22 control subjects. 1 schizophrenic patient and 3 control subjects had high normal responses to metyrapone. The relationship with the dexamethasone suppression test was found to be complex. These preliminary results suggest that the HPA axis activity patterns in psychiatric illness may be more complicated than previously reported.     

EEG changes following scopolamine administration in healthy subjects. Quantitative analysis during rest and photic stimulation.

This study examined the effects of the anticholinergic drug, scopolamine (0.25 mg) in 16 right-handed healthy volunteers. EEGs were recorded before and 60 min after intramuscular administration, and spectral analysis was performed on EEGs recorded at rest and during photic stimulation. Each subject was also evaluated by the Wechsler Memory Scale (WMS; form 1 or 2) before and 90 min after drug administration. In the resting EEG, the scopolamine administration resulted in a significant increase in the absolute power on the delta band (2.0- 3.8 Hz) and in the relative power on the delta and theta-1 bands (4.0-5.8 Hz) mainly over the central and parieto-occipital regions. In contrast, scopolamine significantly decreased the relative alpha-2 band (9.2-12.8 Hz) power mainly over the frontal regions and the absolute alpha-2 band power at most of the recording sites. The analysis of stimulus data showed that scopolamine significantly decreased fundamental photic driving responses elicited by photic stimulation at 15 Hz, with significant effects confined to the occipital regions. These EEG changes occurred in association with a significant reduction in total WMS scores as well as in scores of logical and visual memory subtests. These findings suggest that, in addition to cognitive impairments, central cholinergic dysfunction can cause EEG changes under both nonstimulus and stimulus conditions.     

Effects of RS 86, an orally active cholinergic agonist,on sleep in man

The effect of four oral doses of RS 86, a direct-acting cholinergic agonist, on polygraphic sleep parameters was studied in two groups of 12 healthy male volunteers. Subjects received placebo, 0.25 and 0.50 mg (Study I), or placebo, 0.75 and 1.50 mg (Study II), in a double-blind, balanced, crossover design. While 0.25 and 0.50 mg RS 86 had no effect on electrophysiological correlates of sleep, 0.75 and 1.50 mg altered polygraphic sleep parameters in a dose-dependent fashion: the latency of rapid eye movement (REM) sleep was shortened, REM sleep duration in the first third of the sleep period increased, and slow wave sleep reduced in the first and second thirds of the sleep period. Pulse rate was dose-dependently and significantly increased after RS 86. Subjective sleep experience and the subjects' condition in the morning were not altered. These results suggest that RS 86, in well-tolerated oral doses, has central effects that are partly similar to and partly different from those of other cholinomimetic agents.     

Enhancement of heart rate variability by cholinergic stimulation with pyridostigmine in healthy subjects

The purpose of this study was to determine the effect of the oral administration of pyridostigmine bromide on indices of heart rate variability (HRV) in healthy young volunteers. Seventeen healthy participants (11 men, 6 women; aged 27 +/- 8 y) submitted to a randomized, crossover, double-blind protocol, in which they received 30 mg pyridostigmine bromide (PYR) or placebo orally at 8-hour intervals for 24 hours, on two separate days. Venous blood samples were collected 2 and 24 hours after the first dose for determination of serum cholinesterase activity. Holter tapes were recorded during the 24-hour period and analyzed using a semiautomatic technique to evaluate time- and frequency-domain indices of HRV and to build three-dimensional return maps for later quantification. Symptoms were mild and occurred similarly during administration of PYR and placebo (p = 0.140). Serum cholinesterase activity was reduced by 15% at 2 hours (p = 0.013) and by 14% at 24 hours (p = 0.010) after the first dose of PYR, but not after administration of placebo. Pyridostigmine administration caused a significant increase in the mean 24-hour R-R interval (placebo: 814 +/- 20 msec; PYR: 844 +/- 18 msec; p = 0.003) and in time-domain indices of HRV, such as the standard deviation of all R-R intervals (SDNN; placebo: 151 +/- 9 msec; PYR: 164 +/- 9 msec; p = 0.017), and the percentage of pairs of adjacent R-R intervals differing by more than 50 msec (pNN50; placebo: 12.8 +/- 1.8%; PYR: 13.9 +/- 1.5%; p = 0.029). Pyridostigmine had no significant effect on frequency-domain indices of HRV, but resulted in significant increase in P2, a parasympathetic index derived from the three-dimensional return map (placebo: 93 +/- 13 msec; PYR: 98 +/- 13 ms; p = 0.029). In conclusion, low-dose pyridostigmine reduced mean heart rate and increased HRV during a 24-hour period in healthy young subjects.     

First-cycle REM density in never-depressed subjects with borderline personality disorder.

BACKGROUND: There is much interest in the identification of polysomnographic markers of liability to the mood disorders that may predate the onset of illness in high-risk subjects, and/or remain altered after remission. One such putative marker is rapid eye movement (REM) density during the first REM period. METHODS: Never-depressed subjects with borderline personality disorder (BPD) as a group at high risk for the mood disorders were compared by continuous 48-hour ambulatory electroencephalographic monitoring to age- and gender-matched controls. RESULTS: Subjects with BPD had significantly higher REM density during the first REM period. One man with BPD who later committed suicide had REM density values exceeding the mean value of his group by 2 SD. CONCLUSIONS: These data extend the view that REM density in the first REM period can be a marker of liability to the mood disorders, as it is present in a group of young subjects at heightened risk for depression.     

Cholinergic and noradrenergic neurotransmission: impact on REM sleep regulation in healthy subjects and depressed patients.

The reciprocal interaction model of NonREM- and REM sleep regulation suggests that the cycling alternating pattern of Non-REM- and REM sleep is under the control of noradrenergic/serotonergic and cholinergic neuronal networks. This model was tested in healthy humans by administration of cholinergic agonists/antagonists and noradrenergic antagonists prior to or during sleep. Cholinomimetics like physostigmine, RS 86 and galanthamine provoked an earlier onset of REM sleep, whereas subchronic treatment with scopolamine, a cholinergic antagonist, only led to a heightening of REM density. Simultaneous administration of noradrenergic antagonists with a cholinergic agonist did not provoke a more pronounced REM sleep advance. Comparative studies with the cholinergic agonist RS 86 in depressed patients, schizophrenic patients and patients with other psychiatric disorders revealed the most pronounced REM sleep response in the depressed group. The REM sleep response to cholinergic stimulation in depression did however not predict the treatment response to a differential-therapeutic strategy.     

Effects of scopolamine on interhemispheric EEG coherence in healthy subjects: analysis during rest and photic stimulation.

The present study of coherence analysis, in 16 healthy male volunteers, aged 24-31 years, showed that the administration of 0.25 mg of scopolamine significantly reduced interhemispheric coherence in the delta and beta-1 bands in the resting state. Scopolamine also caused a significant increase both in EEG coherence during PS and in PS-related coherence reactivity in the beta band. In addition, this compound significantly reduced total WMS scores. These findings suggest that, in addition to causing cognitive impairments, central cholinergic dysfunction can alter interhemispheric functional connectivity under both nonstimulus and stimulus conditions.     

Dipyridamole dilates large cerebral arteries concomitant to headache induction in healthy subjects.

Dipyridamole is used for secondary prophylaxis in ischemic stroke and as a vasodilator agent in myocardial scintigraphy. An important side effect to administering dipyridamole is headache. The aim of the current study was to investigate the effects of dipyridamole on cerebral blood flow, large artery diameter, and headache induction. Twelve healthy subjects were included in this single-blind placebo-controlled study in which placebo (0.9% NaCl) and dipyridamole 0.142 mg/kg x min were administered intravenously over 4 minutes 1 hour apart. Blood flow velocity in the middle cerebral artery (Vmax) was recorded by transcranial Doppler and regional cerebral blood flow in the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133Xenon-inhalation. Blood pressure, heart rate, and pCO2 were measured repeatedly. Headache response was scored every 10 minutes on a verbal scale from 0 to 10 (10 = worst). Dipyridamole caused a decrease in pCO2 (P < 0.001). pCO2 corrected rCBFmca was 41.7 +/- 6.9 mL/100 g x min after placebo versus 41.2 +/- 6.9 after dipyridamole (P > or = 0.05). pCO2 corrected Vmca decreased 8.4% +/- 11.7 (P < 0.001) after dipyridamole, indicating a mean 5.6% +/- 6.7 (P = 0.005) relative increase of the arterial diameter. After dipyridamole the median peak headache score was 2 (range 0 to 7) compared with 0 (range 0 to 3) after placebo (P = 0.02). Dilatation of the middle cerebral artery outlasted the headache response. In conclusion, dipyridamole causes a modest pCO2 independent dilatation of the MCA, which is time-linked to the onset, but not to the cessation, of headache.     

Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence.

BACKGROUND: The present study investigated polysomnographically assessed sleep parameters in alcohol-dependent patients after withdrawal and in healthy control subjects during baseline and after a cholinergic stimulation paradigm. The aim of the study was to test whether sleep parameters, especially rapid eye movement (REM) sleep variables, may serve as predictors for relapse in alcohol-dependent patients. METHODS: Forty patients diagnosed with alcohol dependence were admitted to a specialized ward for alcohol withdrawal and were investigated by polysomnography at three time points: 2-3 weeks after withdrawal (T0) and at follow-up investigations 6 (T1) and 12 (T2) months after discharge from the hospital. A subgroup of patients (n = 17) was studied at T0 after challenge with galanthamine, a reversible cholinesterase inhibitor (cholinergic REM induction test, CRIT). Patients were compared with two control groups: a) 30 healthy control subjects (matched for age- and gender-distribution) for comparison at baseline conditions; and b) 17 age- and gender-matched control subjects for comparison with the CRIT. RESULTS: At baseline the patients showed significant disturbances of sleep continuity and sleep architecture (decreased slow-wave sleep, SWS) and exhibited an increase of "REM sleep pressure" (a combined index of REM latency, REM density, and REM sleep percent). Galanthamine provoked significant alterations of sleep continuity, sleep architecture (reduced SWS), and increased most of the components of REM pressure, taking patients and control subjects together. Apart from SWS %SPT (sleep period time) no significant drug-group interactions occurred. Patients who remained abstinent (n = 11) for at least 6 months at follow-up exhibited significantly less abnormalities of REM sleep at T0 compared to the group of patients that relapsed at 6 months follow-up. CONCLUSIONS: It is concluded that increased REM sleep pressure after alcohol withdrawal is a robust predictor of vulnerability to relapse. Thus, a subgroup of alcoholic patients appears to exhibit distinct neurobiological abnormalities assessable by polysomnography that are related to an increased vulnerability for alcoholism and early relapse.     

Cholinergic REM sleep induction by arecoline in normal subjects: relation to thyroid function

Serum thyroid hormones and the speed of rapid eye movement (REM) sleep induction by the central muscarinic agonist arecoline were measured in 21 normal volunteers. The arecoline-REM induction latencies had a modestly significant negative correlation with free thyroxine index. This finding is discussed in the light of observations in animal studies that thyroid hormones stimulate central cholinergic neuronal function.