The influence of the tricyclic antidepressant amitriptyline on periodic limb movements during sleep.

INTRODUCTION: Many antidepressants are associated with periodic limb movements (PLM) during sleep. Although some tricyclic antidepressants, such as amitriptyline, promote sleep and are thus often prescribed as a treatment for sleep disturbances that can accompany depression, it remains unclear whether amitriptyline is associated with PLM. METHODS: 32 healthy males (18-39 years) spent 2 consecutive nights in the sleep lab for polysomnographic recording. During the second night, they received either 75 mg amitriptyline or placebo in a randomized, double-blind, placebo-controlled manner. RESULTS: In subjects receiving amitriptyline but not in subjects receiving placebo, the number of periodic leg movements per h was significantly increased from baseline to intervention night. However, objective polysomnographic sleep parameters (such as the number of awakenings, wake after sleep onset, and sleep efficiency) and subjective sleep perception were not significantly associated with any PLM indices. DISCUSSION: Our findings indicate that amitriptyline can induce or even increase the number of PLM during sleep in healthy subjects. When treating sleep disturbances with amitriptyline, PLM should be considered as a possible cause of insufficient improvement.

[Biological principles of sleep and wake]. / Biologische Grundlagen des Schlafens und Wachens.

Electrophysiologically measurable sleep is divided into rapid eye movement (REM) sleep and nonREM sleep--the latter is further structured into several sleep stages, including deep sleep. This internal sleep regulation is explained by the reciprocal interaction model that was validated in 1975. The interdependence of not only the reciprocal discharge of cholinergic REM-on, but also serotonergic and noradrenergic (REM-off) cell populations distributed over the brain stem results in the alternating pattern of nonREM and REM sleep. The timing of sleep onset and waking is described using the two-process model. Thereby, the theoretical sum of all circadian processes (process C) interacts with the homeostatic sleep drive (process S). Because the occurrence of REM sleep also depends on circadian factors, the decrease of deep sleep during the night is accepted as a physiological correlate of process S. Social activity and daylight synchronize the circadian process with the external 24-h day. With the help of the orexin system, the flip-flop model explains why both sleep and wake can be sustained over longer periods. Dependency on age and physiological short and long sleepers are the most prominent variations of normal sleep behavior. Newer therapeutic concepts in sleep medicine have taken into consideration these biological basics, e.g., in the selection of sleep medication and in the development of new sleep-inducing medications.

[Nicotine. Influence on sleep and its relevance for psychiatry and psychotherapy]. / Nikotin. Einfluss auf den Schlaf und Relevanz für Psychiatrie und Psychotherapie.

BACKGROUND: Nicotine, by its impact on several neurotransmitter systems, influences sleep. Sleep disturbance is a common symptom in different psychiatric disorders and there is a high prevalence of smoking in psychiatric patients. METHODS: Systematic literature search. RESULTS: Symptoms of insomnia are observed during nicotine consumption and its withdrawal. The effects of therapeutic nicotine substitution after smoking cessation on sleep are often masked by withdrawal symptoms. Depressive non-smokers experience an improvement of mood under nicotine administration and in turn, depressive symptoms and sleep impairment during nicotine withdrawal have a negative impact on abstinence rates. CONCLUSION: Sleep disturbance is a comorbid risk factor influencing abstinence during smoking cessation. In depressive patients the complex relationship between affect, sleep, nicotine consumption and its withdrawal should be carefully monitored. In such subgroups of smokers willing to quit this has to be taken care of in therapeutic interventions.

[Restless legs syndrome, periodic limb movements, and psychopharmacology]. / Restless-legs-Syndrom, periodische Gliedmassenbewegungen im Schlaf und Psychopharmakologie.

Restless legs syndrome (RLS) and the often associated periodic limb movement disorder in sleep (PLMD) frequently occur in the general population as a primary disorder. In addition to organic disease, secondary forms are caused by psychotropic medication. Several antidepressants, antipsychotics, lithium, and opioid withdrawal have been shown to induce or exacerbate RLS and PLMD, while several antiepileptics used as mood stabilizers and some benzodiazepines demonstrate therapeutic potential for treating RLS/PLMD. Systematic or controlled studies for evaluating these side effects still do not exist. Among the antidepressants at higher risk of inducing this disorder are selective serotonin reuptake inhibitors, venlafaxine, and some tetracyclic antidepressants. Under medication with some tricyclic substances, periodic limb movements were observed more often. For some antidepressants with differing transmitter profiles such as bupropion RLS/PLMD ameliorating effects or at least neutral effects (Trazodon, Nortriptylin) have been described in small studies. In case of continued of or newly occurring insomnia a thorough history should be taken to identify a possible RLS/PLMD as an intolerable side effect of treatment. A change in medications should be considered if clinically feasible. In case of RLS/PLMD occurring in psychotic patients switching the antipsychotic and additionally using a second line medication such as antiepileptics or a benzodiazepine should be considered.

Evaluation of oxidative stress measurements in obstructive sleep apnea syndrome.

Assessment of reactive oxygen species (ROS) is highly important in neurodegenerative disorders and neuroleptic treatment. However, conflicting results have been reported, which may arise from methodological difficulties. Obstructive sleep apnea (OSA) syndrome with episodic hypoxia-reoxygenation is proposed as a human model for the investigation of ROS measurements. Despite a broad analytical approach comprising lipid peroxidation and amino acid oxidation products, oxidative DNA damage, and activity of the antioxidant defense, only plasma malondialdehyde (MDA) and urinary o,o'-dityrosine seemed to be appropriate, robust biomarkers of oxidative stress, which are also simple enough for routine clinical use. MDA concentrations correlated with a duration of nocturnal desaturation below 85% (r = 0.77, p<0.0005), and o,o'-dityrosine levels decreased after therapy (p<0.05) as a function of baseline concentrations (r = -0.61, p<0.05). Gender effects in ROS generation also have to be considered. At present, we recommend the application of several oxidative stress measurements at different time points, preferably involving plasma MDA and urinary o,o'-dityrosine.

Lisuride treatment of restless legs syndrome: first studies with monotherapy in de novo patients and in combination with levodopa in advanced disease.

In two 4-week polysomnography pilot studies with 10 patients each, we investigated the efficacy of oral lisuride as monotherapy in de novo RLS patients as well as in combination with levodopa in advanced RLS. Daily doses at study end were 0.3 mg lisuride, plus 150 mg levodopa in the combination study. Marked improvements occurred in both studies in different PLM indexes and in the CGI. Levodopa dose could be decreased by 27%. Lisuride might be an efficacious treatment for RLS in general, and in combination with levodopa in advanced stage.

CPAP-therapy effectively lowers serum homocysteine in obstructive sleep apnea syndrome.

Assessment of serum total homocysteine (tHcy) in patients with obstructive sleep apnea (OSA) syndrome is highly relevant since both are strongly associated with stroke and cognitive dysfunction. Seven of 16 untreated OSA patients showed tHcy levels exceeding 11.7 micromol/l. The circadian pattern of serum tHcy in untreated and treated patients (p < 0.001) implied a diagnostic impact of blood sampling time. Treatment with continuous positive airway pressure (CPAP) effectively lowered tHcy levels in patients by about 30% (p < 0.005) and thus probably the (hyper)homocysteinemia-related cognitive dysfunction and the risk for cardio-/cerebrovascular diseases.

The sleep-improving effects of doxepin are paralleled by a normalized plasma cortisol secretion in primary insomnia. A placebo-controlled, double-blind, randomized, cross-over study followed by an open treatment over 3 weeks.

RATIONALE: In primary care, sedating antidepressants are often used for treating insomnia, although their underlying sleep-promoting mechanisms are only incompletely understood. Since enhanced evening and nocturnal plasma cortisol levels are supposed to maintain insomniac sleep complaints, a functional link between sleep and cortisol secretion in the mode of action of antidepressants in insomnia might be suspected. OBJECTIVES: We therefore investigated the effects of the tricyclic antidepressant doxepin on nocturnal sleep and plasma cortisol concentration in ten patients (age 41.3+/-9.5 years) with chronic primary insomnia between 1700 hours and 0800 hours. METHODS: Single infusions of placebo and 25 mg doxepin were applied following a double-blind, randomized cross-over design. Afterward, all patients received 25 mg doxepin p.o. for 3 weeks in an open-study design. RESULTS: Both doxepin application forms improved sleep significantly and reduced mean cortisol levels from 9.0+/-1.7 microg/l (single placebo i.v.) to 7.5+/-1.6 microg/l (single doxepin i.v.) or 7.6+/-2.0 microg/l (subchronic doxepin p.o.). The duration of the quiescent period of the cortisol rhythm was significantly prolonged following both doxepin administrations compared with placebo. CONCLUSIONS: The results implicate that the sleep-improving effects of doxepin are mediated at least in part by a normalization of hypothalamic-pituitary-adrenal axis functions. Although in some patients rebound insomnia and specific side effects must be considered, our findings give a further rationale for the use of antidepressants in the treatment of primary insomnia.

Effects of short-term modified fasting on sleep patterns and daytime vigilance in non-obese subjects: results of a pilot study.

BACKGROUND: Periodically repeated short-term fasting is a frequently practised tradition worldwide. Empirical reports suggest that during fasting periods the quality of sleep and daytime performance are improved. The effects of a home-based 1-week modified fasting on sleep patterns and daytime vigilance and performance were analysed in 15 healthy non-obese volunteers. METHODS: Sleep was measured by polysomnography before and after a 7-day fasting period; sleep inventories with assessment of daytime performance were collected throughout the observation period. Blood samples and urine were drawn at the beginning and at the end of fasting. RESULTS: 13 subjects (12 females, 1 male; age 41.2 +/- 13.4 years; BMI 23.9 +/- 4.2 kg/m(2)) completed the fasting period; weight decreased from 66.5 +/- 11.7 kg to 63 +/- 11.9 kg. Compared to baseline, a significant decrease in arousals, a decrease in periodic leg movements (PLM) and a non-significant increase in REM sleep were observed at the end of fasting. Subjective sleep ratings showed a fasting-induced increase in global quality of sleep, daytime concentration, vigour and emotional balance. Clinical laboratory tests showed a decrease in serum magnesium; urinary melatonin excretion decreased moderately. CONCLUSION: This open pilot study demonstrates that along with a decrease in sleep arousals a 1-week fasting period promotes the quality of sleep and daytime performance in non-obese subjects. The observed decrease in PLM might point to a nutritional modification of brain dopaminergic functions. In terms of evolutionary development, an improved daytime performance during periods of food deprivation could have been beneficial for the success in search for food.

The short-term effects of fasting on the neuroendocrine system in patients with chronic pain syndromes.

It is commonly reported that short term fasting leads to mood enhancement and emotional harmonisation. We investigated psychosocial well-being and the neuroendocrine response, assessed by nightly urinary excretion of cortisol and catecholamines, in 28 inpatients with chronic pain syndromes during and after a one-week modified fast. Twenty-two of the patients (51.4 +/- 2.7 years, BMI 26.8 +/- 1.0 kg/m2) participated in a 7-day fast with daily intake of 300 kcal/day, six control patients (47.5 +/- 4.0 years; BMI 22.9 +/- 1.1 kg/m2) received a vegetarian-based diet. With fasting significant increases of the urinary concentration of noradrenaline (17.8 +/- 3.0-27.8 +/- 3.8 microg/ml), adrenaline (1.5 +/- 0.2-3.4 +/- 0.7 microg/ml) and cortisol (26.1 +/- 3.7-40.7 +/- 6.1 microg/ml) were observed, whereas controls showed no significant endocrine changes. The neuroendocrine response to fasting was pronounced in younger subjects (age <50 years) and in the presence of a BMI >25 kg/m2, moreover the increase in cortisol excretion was significantly higher in subjects with lower baseline cortisol levels. Mood and well-being increased non-significantly in both groups. Fasting was well tolerated, and regarded as beneficial by most fasting patients. Our results show that short-term fasting leads to neuroendocrine activation and may suggest that the extent of this response is dependent on the individual metabolic and endocrine state at baseline.

Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study.

In recent years, sedating antidepressants have been increasingly used to treat primary insomnia. Up to now, only one open pilot study with trimipramine and one double-blind placebo-controlled study with doxepin have provided scientific support for this approach in treating primary insomnia. In order to test the hypothesis that sedating antidepressants are useful in the treatment of primary insomnia, the effect of trimipramine on objectively and subjectively measured parameters of sleep was investigated in a double-blind placebo- and lormetazepam-controlled study in a sample of 55 patients with primary insomnia attending outpatient sleep-disorder clinics. Trimipramine was selected since it has shown positive effects on sleep continuity with a lack of REM sleep suppression in studies on depressed patients and in one pilot study on patients with primary insomnia. Trimipramine at an average dose of 100 mg over a period of 4 weeks significantly enhanced sleep efficiency, but not total sleep time (which had been the primary target variable) compared to placebo as measured by polysomnography. Changes in objective sleep parameters were paralleled by changes in subjective sleep parameters. Trimipramine did not suppress REM sleep. Lormetazepam decreased wake time and sleep stage 3 and increased REM sleep compared to placebo. After switching trimipramine to placebo, sleep parameters returned to baseline. There was no evidence of any rebound effect from trimipramine. Side effects from trimipramine were only marginal. This first double-blind placebo-controlled study with trimipramine suggests its efficacy in the treatment of primary insomnia. However, due to the large intra- and interindividual variance in the parameters of interest before and during treatment a larger sample size would have been necessary to strengthen the validity of our findings.

Biochemical markers of cerebrovascular injury in sleep apnoea syndrome.

Sleep apnoea syndrome (SAS) is a known risk factor for vascular diseases and stroke. Structural brain damage, manifesting as an overt neurological deficit or more subtly as cognitive dysfunction, is a frequent symptom in SAS. The presence of a biochemical marker of cerebral injury would be of great benefit in SAS to screen for even small brain damage and to monitor efficiacy of therapy. Therefore, in 10 patients with mild SAS (age 50.8+/-9.9 yrs, respiratory disturbance index (RDI) 18+/-3.6, lowest arterial oxygen saturation (min Sa,O2) 80.5+/-4.06%) and nine patients with severe SAS (age 50.3+/-11.5 yrs, RDI 75.4+/-21.7, min Sa,O2 56.56+/-14.58%), serum concentrations of neuron-specific enolase (NSE), S-100beta protein, and beta-trace were measured just before and after sleep using commercially available assays. Only serum levels in the normal range could be found, independent of when the blood was taken or the degree of SAS. Structural cerebral injury caused by sleep apnoea syndrome in patients without neurological symptoms or previous cerebrovascular events may be too small to produce a measurable increase in S-100beta, neuron-specific enolase and beta-trace serum concentrations or subclinical cerebral damage may be outside the lower detection limits of the analytical methods which were used. There is a need for biochemical markers and more sensitive methods for detecting small cerebral injury in sleep apnoea syndrome.

Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study.

BACKGROUND: Over recent years, the use of antidepressants for the symptomatic treatment of insomnia has grown substantially, but controlled studies are still lacking. Our study is the first investigation to prove objective efficacy and tolerability of low doses of a sedating antidepressant in a randomized, double-blind, and placebo-controlled manner in patients with primary insomnia. METHOD: Forty-seven drug-free patients meeting DSM-IV criteria for primary insomnia (mean +/- SD duration of complaints = 11.2+/-9.7 years) received either 25-50 mg of the tricyclic antidepressant doxepin or placebo for 4 weeks followed by 2 weeks of placebo withdrawal. Sleep was measured by polysomnography at baseline and the first night of application, at 4 weeks of treatment and the first to third night of withdrawal, and after 2 weeks of withdrawal. RESULTS: In the doxepin-treated patients who completed the study (N = 20, 47.6+/-11.3), medication significantly increased sleep efficiency after acute (night 1, p < or = .001) and subchronic (night 28, p < or = .05) intake compared with the patients who received placebo (N = 20, 47.4+/-16.8 years of age). Latency to sleep onset was not affected since the patients had normal baseline sleep latencies. Investigators found doxepin to cause significantly (p < or = .05) better global improvement at the first day of treatment. Patients rated sleep quality (p < or = .001) and working ability (p < or = .005) to be significantly improved by doxepin during the whole treatment period. Overall rebound in sleep parameters was not observed, but patients with severe rebound insomnia were significantly more frequent in the doxepin group (night 29, p < .01, night 30, p < or = .01; night 31, p < or = .05). No significant group differences in side effects were found, but 2 doxepin-treated patients dropped out of the study due to specific side effects (increased liver enzymes, leukopenia, and thrombopenia). CONCLUSION: The results support the effectiveness of low doses of doxepin to improve sleep and working ability in chronic primary insomniacs, although subjective effects were light to moderate, and in some patients, rebound insomnia and specific side effects have to be considered.

Neuroendocrine dysregulation in primary insomnia.

Recent research has pointed to a functional link between stress, disturbed sleep, psychiatric disorders, ageing, and neuroendocrine dysfunctions. In particular, increased activation of the hypothalamic-pituitary-adrenal (HPA) axis--expressed as elevated plasma cortisol levels--was shown in physiological ageing and patients with psychiatric disorders. We found increased evening and nocturnal plasma cortisol concentrations in patients with primary insomnia. Considering that both ageing and psychiatric disorders are commonly associated with sleep disturbances, our results implicate that elevated cortisol concentrations are a rather unspecific feature of disturbed sleep. Furthermore, our data revealed a strong positive correlation between evening cortisol secretion and the number of nocturnal awakenings in both insomniac patients and controls. Since nocturnal exposure to increased HPA activity promotes sleep fragmentation even in healthy controls, increased evening cortisol levels may be a crucial factor in inducing and maintaining sleep disturbances. We therefore propose a model of HPA dysregulation in insomnia. This model is based on the arousal theory of insomnia and the strong correlation between evening cortisol secretion and sleep fragmentation as a pathophysiological mechanism of a vicious cycle of insomnia. In patients with long-lasting insomniac complaints we found decreased nocturnal plasma melatonin levels thereby indicating a labilisation of circadian rhythm functions. Taken together, the neuroendocrine dysregulation seems to be more expressed in chronic insomnia than in acute insomnia and may be a contributing factor in maintaining disturbed sleep.

Nocturnal melatonin secretion and its modification by treatment in patients with sleep disorders.

Data on the circadian melatonin secretion in sleep disordered patients and effects of sleep medication on melatonin are still missing. We studied plasma melatonin concentration, sleep, and effects of some hypnotics in 15 patients and 10 controls. Nocturnal melatonin levels were significantly decreased in patients with a more than five years history of sleep complaints compared to controls or patients with a shorter duration of illness. Independent of their sleep promoting properties drugs increased or decreased nocturnal melatonin in controls and patients. Patients with chronic sleep-wake rhythm disorders showed altered relations between their circadian melatonin secretion pattern and sleep. We conclude that nocturnal melatonin secretion is primarily independent of sleep regulation but represents a neuroendocrine feature of chronically disturbed sleep.

Effect of continuous melatonin infusions on steady-state plasma melatonin levels, metabolic fate and tissue retention in rats under near physiological conditions.

The fate and disposition of melatonin released into the circulation is still poorly understood, and almost all current knowledge is derived from measurements made after one single, often very large dose of labeled melatonin. In continuous infusion experiments in freely moving rats, 500 ng melatonin/mL hr had to be infused in order to elevate the circulating hormone from low daytime levels to the 10-fold higher nocturnal steady state concentrations. To study the fate and tissue accumulation of the infused melatonin, tritiated melatonin was added to the infusion solution, and the retention of [3H]-melatonin and chloroform-insoluble [3H]-melatonin-metabolites were measured in almost all body tissues and their subcellular compartments immediately at the end of the infusion period and six hours later. A considerable amount of the infused melatonin was found in the gut and in all tissues, some melatonin was covalently attached to proteins.

Rebound insomnia after hypnotic withdrawal in insomniac outpatients.

The effect of abrupt medication withdrawal (no-pill discontinuation) was investigated in 1507 insomniacs using the patients' self-ratings on visual analogue scales. Drug discontinuation followed a 28-day treatment period with either 7.5 mg zopiclone, 0.25 mg triazolam, 1.0 mg flunitrazepam, or placebo in a randomized, double-blind, parallel group, multicenter study in private practice. Deterioration below individual pretreatment values (no-pill baseline) in at least one of three subjective parameters of sleep quality (sleep latency, total sleep time, nocturnal awakenings) and three parameters of daytime well-being (morning freshness, daytime tiredness, anxiety) were defined as rebound. The number of patients with rebound (rebound rate) was analyzed for every day of a 2-week posttreatment period. The overall rebound rate was higher in the placebo group (p < or = 0.001) than in each group treated with active drugs. Rebound rates affecting sleep quality were higher for placebo than for zopiclone (p < or = 0.001) and for flunitrazepam (p < or = 0.05). Rebound rates were smaller for zopiclone (p < or = 0.001) and flunitrazepam (p < or = 0.01) than for triazolam. Rebound in at least one item per day appeared in 21.5% (sleep quality) and 25.5% (daytime well-being) of the patients. Rebound decreased with increasing numbers of items of sleep quality or daytime well-being. Patients who did not respond to treatment showed higher rebound rates than those who were treatment responders (p < or = 0.001). Concerning treatment nonresponders, highest rebound was seen in the placebo group, whereas rebound was lowest in placebo responders. These results show that pill discontinuation itself may worsen sleep and daytime well-being in the sense of a rebound phenomenon. Furthermore, the number of patients with rebound remained at a high and varying level during the whole posttreatment period. This result indicates that a deterioration of sleep after drug withdrawal is not apparent during a few days but may last for longer periods in some patients and is modified by marked night-to-night variations.

Effect of continuous melatonin infusions on steady-state plasma melatonin levels in rats under near physiological conditions.

It was the aim of this study to measure the actual amount of melatonin required for elevating the circulating hormone from low daytime levels to the 10-fold higher nocturnal steady-state concentrations in rats. For this purpose, escalating doses of melatonin were continuously infused into the right jugular vein and blood samples were repeatedly drawn from the left jugular vein for a period of 2 hr in freely moving catheterized rats. In order to achieve an about 10-fold elevation of the plasma melatonin concentration, 500 ng melatonin/hr had to be infused, i.e., about 300 times the normal nocturnal melatonin content of the pineal. Infusions of up to 61 ng melatonin/hr (equivalent to the melatonin content of 40 pineals at darkness) failed to cause a significant rise of the low daytime steady-state concentrations in the blood. If the dose of 500 ng melatonin/h was infused at night, a less-pronounced rise of the blood levels was observed, as compared to that caused by the infusion of the same dose during daytime. No differences were found in the rate of metabolism between daytime and nighttime. The results of this study indicate 1) that the low basal concentrations of melatonin in the blood are not affected by an increased melatonin supply up to a certain critical threshold, 2) that the rat pineal gland would have to release all its melatonin content almost every 10 sec in order to sustain the elevated steady-state level of melatonin in the circulation during the dark period, and 3) that significant day/night differences exist in the disposition of circulating melatonin if administered in near physiological amounts and under near physiological conditions.