OBJECTIVE: Because the initial phase of treatment of depression with a selective serotonin reuptake inhibitor is often complicated by a delayed onset of action of the antidepressant or severe insomnia or both, we investigated whether tryptophan, an amino acid with both antidepressant-augmenting and hypnotic effects, would benefit patients with depression at the beginning of treatment with fluoxetine. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Thirty individuals with major depressive disorder. INTERVENTIONS: Treatment over 8 weeks with 20 mg of fluoxetine per day and either tryptophan (2 to 4 g per day) or placebo. OUTCOME MEASURES: Mood was assessed using the 29-item Hamilton Depression Rating Scale (HDRS-29) and the Beck Depression Inventory (BDI). Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using standard procedures. RESULTS: During the first week of treatment, there was a significantly greater decrease in HDRS-29 depression scores, and a similar trend in BDI scores, in the tryptophan/fluoxetine group than in the placebo/fluoxetine group. No significant differences were noted at later time points. With respect to sleep measures, there was a significant group-by-time interaction for slow-wave sleep at week 4. Further analysis revealed a significant decrease in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group, but not in the tryptophan/fluoxetine group. No cases of serotonin syndrome occurred, and the combination was well tolerated, although the 4 g per day dosage of tryptophan produced daytime drowsiness. CONCLUSIONS: Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep. Further large-scale studies are needed to confirm these initial findings.

This report describes the case of a 44-year-old woman presenting to a Sleep and Alertness clinic with symptoms of narcolepsy. The patient had clinical and polysomnographic features of narcolepsy, which disappeared after disclosure of severe psychological stress. Following a discussion of the differential diagnosis of narcolepsy, alternative diagnoses are considered. The authors suggest that the patient had a hysterical conversion disorder, or "pseudo-narcolepsy." Careful inquiry into psychological factors in unusual cases of narcolepsy may be warranted.

Most patients with asthma waken with nocturnal asthma from time to time. To assess morbidity in patients with nocturnal asthma nocturnal sleep quality, daytime sleepiness, and daytime cognitive performance were measured prospectively in 12 patients with nocturnal asthma (median age 43 years) and 12 age and intellect matched normal subjects. The median (range) percentage overnight fall in peak expiratory flow rate (PEF) was 22 (15 to 50) in the patients with nocturnal asthma and 4 (-4 to 7) in the normal subjects. The patients with asthma had poorer average scores for subjective sleep quality than the normal subjects (median paired difference 1.1 (95% confidence limits 0.1, 2.3)). Objective overnight sleep quality was also worse in the asthmatic patients, who spent more time awake at night (median difference 51 (95% CL 8.1, 74) minutes), had a longer sleep onset latency (12 (10, 30) minutes), and tended to have less stage 4 (deep) sleep (-33 (-58, 4) minutes). Daytime cognitive performance was worse in the patients with nocturnal asthma, who took a longer time to complete the trail making tests (median difference 62 (22, 75) seconds) and achieved a lower score on the paced serial addition tests (-10 (-24, -3)). Mean daytime sleep latency did not differ significantly between the two groups (2 (-3, 7) minutes). It is concluded that hospital outpatients with stable nocturnal asthma have impaired sleep quality and daytime cognitive performance even when having their usual maintenance asthma treatment.

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A randomised, double blind, placebo controlled crossover trial of high dose nebulised ipratropium was carried out in 10 asthmatic patients with documented nocturnal bronchoconstriction. Patients received nebulised saline or ipratropium 1 mg at 10 pm and 2 am on two nights. Absolute peak flow (PEF) rates were higher throughout the night after the patients had received ipratropium (at 2 am, for example, mean (SEM) PEF was 353 after ipratropium and 285 l/min after placebo). The fall in PEF overnight, however, was similar with ipratropium and placebo. Patients were given a further 1 mg nebulised ipratropium at 6 am on both nights. There was a significant overnight fall in PEF on the ipratropium night even when comparisons were made between the times that maximal cholinergic blockade would be expected, PEF falling between 11.30 pm and 7.30 am from 429 to 369 l/min. The percentage increase in PEF, though not the absolute values, was greater after ipratropium at 6 am than at 10 pm. These results confirm that ipratropium raises PEF throughout the night in asthmatic patients, but suggest that nocturnal bronchoconstriction is not due solely to an increase in airway cholinergic activity at night.

Heart rate variability was measured in 77 healthy controls and 343 diabetic patients by a count of the number of beat-to-beat differences greater than 50 ms in the RR interval during a 24 hour ambulatory electrocardiogram. In the healthy controls the lower 95% tolerance limits for total 24 hour RR interval counts were approximately 2000 at age 25, 1000 at 45, and 500 at 65 years. Six controls confined to bed after injury had normal 24 hour patterns of RR counts, while eight other controls showed loss of diurnal variation in both heart rate and RR counts during a period of sleep deprivation. RR counts in ten controls on and off night duty increased during sleep whenever it occurred. Nearly half (146) the 343 diabetic patients had abnormal 24 hour RR counts. The percentage of abnormal RR counts increased with increasing autonomic abnormality assessed by a standard battery of tests of cardiovascular autonomic function. A quarter of those with normal cardiovascular reflex tests had abnormal 24 hour RR counts. There were close correlations between 24 hour RR count results and the individual heart rate tests (r = 0.6). The assessment of cardiac parasympathetic activity by 24 hour RR counts was reliable. The diurnal variations in RR counts seen in the controls were probably related to sleep rather than either posture or time of day. The method was more sensitive than conventional tests of cardiovascular reflexes.

Breathing patterns early and late in the night, at the same sleep stage, were compared in six healthy subjects and 15 adults with nocturnal asthma, to try to identify changes of overnight bronchoconstriction, and breathing patterns at different sleep stages, to see whether there were changes related to sleep stages that were indicative of bronchoconstriction. Despite an average 31% fall in FEV1 overnight in the patients with asthma, neither breathing frequency nor expiratory time, which might be expected to change during bronchoconstriction, was different early in the night from late in the night, nor did they differ between sleep stages. There was no evidence of asynchronous movement of the chest and abdomen in any patient. This study did not identify any abnormality of breathing pattern that would indicate the development of nocturnal asthma without the need to awaken the patient.

Patients with asthma often wheeze at night and they also become hypoxic during sleep. To determine whether ketotifen, a drug with sedative properties, is safe for use at night in patients with asthma, we performed a double blind crossover study comparing the effects of a single 1 mg dose of ketotifen and of placebo on arterial oxygen saturation (SaO2), breathing patterns, electroencephalographic (EEG) sleep stage, and overnight change in FEV1 in 10 patients with stable asthma. After taking ketotifen, the patients slept longer and their sleep was less disturbed than after taking placebo, true sleep occupying 387 (SEM 8) minutes after ketotifen and 336 (19) minutes after placebo (p less than 0.02). On ketotifen nights the patients had less wakefulness and drowsiness (EEG sleep stages 0 and 1) and more non-rapid eye movement (non-REM) sleep than on placebo nights, but the duration of REM sleep was similar on the two occasions. Nocturnal changes in SaO2, the duration of irregular breathing, and overnight change in FEV1 were unaffected by ketotifen.

Nocturnal cough and wheeze are common in asthma. The cause of nocturnal asthma is unknown and there is conflicting evidence on whether sleep is a factor. Twelve adult asthmatic subjects with nocturnal wheeze were studied on two occasions: on one night subjects were allowed to sleep and on the other they were kept awake all night, wakefulness being confirmed by electroencephalogram. Every patient developed bronchoconstriction overnight both on the asleep night, when peak expiratory flow (PEF) fell from a mean (SE) of 418 (40) 1 min-1 at 10 pm to 270 (46) 1 min-1 in the morning, and on the awake night (PEF 10 pm 465 (43), morning 371 (43) 1 min-1). The morning values of PEF were, however, higher (p less than 0.1) after the awake night and both the absolute and the percentage overnight falls in PEF were greater when the patients slept (asleep night 38% (6%), awake night 20% (4%); p less than 0.01). This study suggests that sleep is an important factor in determining overnight bronchoconstriction in patients with nocturnal asthma.

Many patients with asthma are troubled by nocturnal wheeze. The cause of this symptom is unknown, but sleep is an important factor. A study was carried out to determine whether nocturnal bronchoconstriction is related to any specific stage of sleep. Eight asthmatics with nocturnal wheeze and eight control subjects performed forced expiratory manoeuvres immediately after being woken from rapid eye movement (REM) or non-REM sleep, wakings being timed to differentiate temporal effects from those related to the stage of sleep. The control subjects showed no significant temporal bronchoconstriction or bronchoconstriction related to the stage of sleep. All patients showed bronchoconstriction overnight, the mean peak expiratory flow rate falling from 410 (SEM 50) 1/min before sleep to 186 (49)1/min after sleep. After the patients had been woken from REM sleep the forced expiratory volume in one second was on average 300 ml lower (p less than 0.02) and peak expiratory flow rate 45 1/min lower (p less than 0.03) than after they had been woken from non-REM sleep. As wakenings from REM sleep were 21(8) minutes later in the night than those from non-REM sleep multivariate analysis was performed to differentiate temporal effects from those related to the stage of sleep. This showed that the overnight decreases in forced expiratory volume in one second and peak expiratory flow rate were significantly related both to time and to REM sleep. This study suggests that asthmatics may suffer bronchoconstriction during REM sleep.

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To investigate whether mast cell degranulation was important in producing nocturnal asthma, the effect of a single high dose of nebulised sodium cromoglycate on overnight bronchoconstriction, oxygen saturation, and breathing patterns in eight patients with nocturnal wheeze was examined. The study took the form of a double blind placebo controlled crossover comparison. Treatment with cromoglycate did not reduce the overnight fall in FEV1 or FVC, although it was associated with improved nocturnal oxygenation. This study suggests that mast cell degranulation may not be important in the pathogenesis of nocturnal asthma.