G. Hajak

Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia.

Recent research provides evidence for an interaction between sleep and the activation of the hypothalamic-pituitary-adrenal (HPA)-axis, but detailed studies in patients are still missing. We investigated hourly evening and nocturnal plasma cortisol secretion and sleep in seven male patients with severe chronic primary insomnia and age- and gender-matched controls. Evening and nocturnal cortisol levels were significantly increased in patients. Evening cortisol correlated with the number of nocturnal awakenings in patients and controls. Additionally, patients showed significant correlations between sleep parameters and the first 4 h of nocturnal cortisol secretion. These results are indicative of changes in the HPA system in insomnia and may reflect a pathophysiological mechanism of chronic insomnia resulting in a vicious cycle of both disturbed HPA functions and chronic insomnia according to the arousal hypothesis of insomnia.

Nocturnal myoclonus syndrome (periodic movements in sleep) related to central dopamine D2-receptor alteration.

The nocturnal myoclonus syndrome (NMS) consists of stereotyped, repetitive jerks of the lower limbs that occur during sleep or wakefulness. NMS is often related with restless-legs syndrome (RLS) and can cause severe sleep disturbances and daytime sleepiness. The efficacy of dopamine agonists in the treatment points to a dopaminergic dysfunction in NMS. We investigated the central dopamine D2-receptor occupancy with [123I] labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) (a highly selective CNS D2 dopamine receptor ligand) ([123I]IBZM) and single photon emission tomography (SPET) in 20 patients with NMS and in 10 healthy controls. In most of the patients with NMS there was a lower [123I]IBZM binding in the striatal structures compared to controls. The results indicate that NMS is related to a decrease of central D2-receptor occupancy.

Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia

Abstract: Polysomnographic sleep patterns and melatonin secretion were investigated in 10 patients (age: 41.3 ± 9.5 years) who suffered from chronic primary insomnia and complained predominantly about difficulties in maintaining sleep and in five healthy controls (age 27.2 ± 0.7 years). Nocturnal plasma melatonin concentrations were obtained hourly, measured by direct radioimmunoassay and statistically compared between insomniacs and controls with age as a covariate. Plasma melatonin levels in the patient group tended to begin increasing earlier in the evening and were significantly (P ± 0.01) lower during the middle of the night (peak value 82.5 ± 26.5 pg/ml) than in the healthy controls (peak value 116.8 ± 13.5 pg/ml). Among the patients, the most severely reduced nocturnal plasma melatonin levels were found in those patients with a history of sleep disturbance lasting for longer than five years (N = 6; age 41.8 ± 11.7 years; duration 15.3 ± 5.9 years; peak value 72.1 ± 25.0 pg/ml); whereas those chronic insomniacs affected for fewer than five years had relatively higher nocturnal levels (N = 4; age 40.6 ± 6.5 years; duration 3.8 ± 1.5 years; peak value 98.2 ± 23.9 pg/ml). These results show that the circadian rhythm of melatonin secretion is disturbed in patients with chronic primary insomnia, and that the nocturnal plasma melatonin secretion is increasingly more affected the longer the patients are unable to maintain a regular sleep pattern.

The sleep-improving effects of doxepin are paralleled by a normalized plasma cortisol secretion in primary insomnia

RationaleIn 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.ObjectivesWe therefore investigated the effects of the tricyclic antidepressant doxepin on nocturnal sleep and plasma cortisol concentration in ten patients (age 41.3±9.5xa0years) with chronic primary insomnia between 1700xa0hours and 0800xa0hours.MethodsSingle infusions of placebo and 25xa0mg doxepin were applied following a double-blind, randomized cross-over design. Afterward, all patients received 25xa0mg doxepin p.o. for 3xa0weeks in an open-study design.ResultsBoth doxepin application forms improved sleep significantly and reduced mean cortisol levels from 9.0±1.7xa0µg/l (single placebo i.v.) to 7.5±1.6xa0µg/l (single doxepin i.v.) or 7.6±2.0xa0µg/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.ConclusionsThe 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.

The metabolic fate of infused L-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites*

Abstractl-Tryptophan (Trp) was widely used as a natural tool for the support of serotonin-mediated brain functions and as a challenge probe for the assessment of serotonin-mediated neuroendocrine responses. The metabolic fate of the administered Trp and the kinetics of the accumulation of Trp metabolites in the circulation, however, have never thoroughly been investigated.This study describes the time- and dose-dependent alterations in the plasma levels of various Trp metabolites and large neutral amino acids after the infusion of Trp to healthy young men (1, 3 and 5 g; placebo-controlled, double-blind, cross-over study during day- and night-time).The major Trp metabolites (kynurenine, indole acetic acid and indole lactic acid) in plasma increased dose-dependently but rather slowly after Trp administration to reach their maximal plasma levels (up to 10-fold after the 5 g dose) at about 3 h p.i., and remained at an elevated level (about 5-fold) for up to 8 h. N-acetyl-Trp and 5-hydroxy-Trp rose rapidly and massively after Trp infusions, at the 5 g dose more than 200- and 20-fold, respectively, and declined rapidly to about 5-fold baseline levels within 2 h. Whole blood serotonin levels were almost unaffected by the Trp infusions. A rather slow increase of 5-hydroxyindole acetic acid was seen, reaching maximum values (3-fold at the 5 g dose) at about 2 h after the infusion of Trp. Additionally, a dose-dependent rise of circulating melatonin was observed afterl-Trp infusions. The administration ofl-Trp caused a depletion of the concentrations of the other large neutral amino acids and a dose dependent decrease of the ratio between plasma tyrosine and the sum of the plasma concentrations of the other large neutral amino acids. Apparently, none of the existing pathways of peripheral Trp metabolism is saturated by its substrate, Trp in men. At least some of the central effects reported afterl-Trp administration may be mediated by the Trp-stimulated formation of neuroactive metabolites or by the decreased availability of tyrosine for catecholamine synthesis.

Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-Dopa

SummaryA double-blind randomized crossover study of 0.125 mg Pergolide (Lilly®) at bedtime versus 250 mg L-Dopa + Carbidopa (Roche®) was conducted in 16-day phases in 11 patients with idiopathic restless legs syndrome. Two patients reported a partial and 9 patients a complete relieve of motor restlessness while receiving Pergolide. Only 1 patient experienced an improvement of restlessness after L-Dopa. The patients showed polysomnographically a mean decrease in NMS cluster disturbed time by 45% from control on L-Dopa (p < 0.025) and by 79% from control on Pergolide (p < 0.001). In addition, Pergolide increased the total sleep time compared to L-Dopa (p < 0.05). In conclusion, the dopamine agonist Pergolide is superior to L-Dopa in the treatment of RLS and NMS.

Single photon emission tomography (SPET) imaging of dopamine D2 receptors in the course of dopamine replacement therapy in patients with nocturnal myoclonus syndrome (NMS)

Single photon emission tomography (SPET) permits the in vivo measurements of regional cerebral radioactivity in the human brain following the administration of compounds labeled with photon-emitting isotopes. According to our SPET findings of a reduced binding of [123I]labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) (a highly selective CNS D2 dopamine receptor ligand) to D2 dopamine receptors in striatal structures in untreated patients with nocturnal myoclonus syndrome (NMS) it seemed to be of interest to investigate whether there are changes in D2 receptor binding under dopamine replacement therapy or not. We studied the uptake and distribution of [123I]IBZM before and in the course of dopamine replacement therapy in four patients with severe insomnia caused by a nocturnal myoclonus syndrome (NMS). We found an increase of the IBZM binding to D2 receptors in the course of treatment, which was associated with an improvement of sleep quality. Reasons for this are discussed. The [123I]IBZM SPET technique in conclusion offers an interesting tool for in vivo investigations of functional changes in the dopaminergic neurotransmitter system in longitudinal studies.

Disturbed sleep in children with Tourette syndrome: A polysomnographic study

OBJECTIVEnTo evaluate objective data on sleep quantity/quality and motor activity during night sleep in children with Tourette syndrome (TS).nnnMETHODnPolysomnography of 17 unmedicated TS children (ages: 7;11-15;5, mean: 11;10 years) without comorbid attention-deficit hyperactivity disorder (ADHD) was compared with 16 age-, sex- and IQ-matched healthy controls. Sleep analyses according to the procedure of Rechtschaffen and Kales were supplemented by counting epochs with short arousal-related movements (<or=15 s), thus allowing to calculate correlations between motor activity and sleep parameters.nnnRESULTSnChildren with TS demonstrated changes in sleep parameters, including longer sleep period time, longer sleep latency, reduced sleep efficiency, and prolonged wakefulness after sleep onset. Their sleep profiles showed significantly more time awake and less sleep stage II. However, REM sleep variables, slow-wave sleep, and number of sleep stage changes were unaffected. Movement time was similar in both groups, but epochs with short arousal-related movements were increased in TS. Further analyses showed no significant correlations between sleep parameters and nighttime nontic movements, level of psychopathology or tic severity during daytime. Periodic limb movements during sleep (PLMS) were only seen in one TS patient (low PLMS index of 7.8/h).nnnCONCLUSIONSnChildren with TS have disturbed sleep quality with increased arousal phenomena, which both may be intrinsic to the disorder and might trigger tics and other behavioral problems during daytime. This indicates the need for sleep evaluation in patients with TS.

EFFECTS OF CHRONIC TREATMENT WITH METHADONE AND NALTREXONE ON SLEEP IN ADDICTS

Previous studies have described sleep disturbance secondary to chronic opiate use and abuse. Drug-dependency insomnia is of interest because chronic sleep disturbances can promote depressive symptoms which could lead to a drug relapse. For the first time we compared the polysomnographic parameters of 10 methadone-substituted outpatients and 10 naltrexone-treated outpatients. Methadone (μ-opioid agonist) produced a marked fragmentation of the sleep architecture with frequent awakenings and a decrease in EEG arousals. In comparison with methadone and controls, the naltrexone (μ-opioid antagonist) group showed the shortest sleep latency and the longest total sleep time. These data indicate that μ-agonists and μ-antagonists have different effects on sleep. The implications, especially the involvement of opioid-dopamine interactions on sleep and movements during sleep, are discussed.

First results on daytime submandibular electrostimulation of suprahyoidal muscles to prevent night-time hypopharyngeal collapse in obstructive sleep apnea syndrome.

Daytime submandibular electrostimulation (dSE) of suprahyoidal muscles was applied to prevent sleep-associated collapse of the tongue into the hypopharyngeal airway. By placing the stimulatory electrodes intra- and extraorally, recruitment of stimulated muscle fibers at low current densities was improved. The significant impact of electrostimulation on suprahyoidal muscle force was initially demonstrated in healthy controls as compared to placebo-treated volunteers. The morphology of suprahyoidal muscles was not affected by this treatment. A patient with obstructive sleep apnea syndrome initially presented with a respiratory disturbance index (RDI) of 13.2, an oxygen desaturation index of 23 and a minimal oxygen saturation of 75%. After two weeks of placebo treatment (TENS-stimulation), respiratory parameters remained unchanged. Two weeks of dSE treatment, however, improved the RDI to 3.9, the oxygen desaturation index from 23 to 2.8 and the minimal oxygen saturation from 75% to 88%. 3D-sonography showed considerable hypertrophy of the stimulated muscles. These results indicate that dSE may prevent episodes of apnea induced by sleep-associated hypopharyngeal collapse of the tongue.