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In individuals anatomically predisposed to upper airway obstruction during sleep, the openness of the airway depends on the activity of upper airway dilator muscles. This is reduced in sleep, especially REM sleep. The authors propose this results from withdrawal of an excitatory influence, specifically serotonergic neuronal input from a specific brainstem nucleus, the caudal raphe nucleus, which supplies serotonin to upper airway motor nerve cells and the firing of which is decreased in sleep, especially REM sleep. If so, the administration of drugs antagonizing (opposing) serotonin activity should result in disordered breathing events, even during wakefulness. The authors decided to test this in an animal model of sleep-disordered breathing, the English bulldog, which has a significantly narrowed upper airway, daytime hypersomnolence, shortened sleep latency, and frequent sleep-disordered breathing events especially during REM sleep--in other words, sleep apnea. Furthermore, normal breathing during waking and sleep in these dogs is associated with increased upper airway muscle activity, as it is in people with sleep apnea.
To test their hypothesis, the authors chose as drugs methysergide, a broad-spectrum serotonin antagonist, and ritanserin, a more specific antagonist of certain serotonin receptors especially linked with upper airway muscle activity. They measured resulting changes in upper airway dilator muscles and the diaphram as well as oxyhemoglobin saturation, and in some animals upper airway size and chest wall movement.
I will omit the specific procedures by which animals were monitored. Prior to the trial, each dog underwent a sleep study which showed an average RDI of 30 (SD=5) during REM sleep and an average oxygen saturation low of 78% (SD=2%). One of the eight dogs tested was minimally affected by sleep apnea but was included in the study anyway.
Both drugs were subsequently tested on the animals in the awake state. They were administered intravenously, at increasing dose levels up to either a total of 1 mg/kg or a desaturation of 85%. Neither drug showed any significant effect on the animals' behavior, except for occasional staring episodes after methysergide.
Ritanserin consistently reduced peak muscular activity in the geniohyoid muscle by about 40%, without any relation of dosage to degree of suppression. It also reduced sternohyoid muscle activity, by about 30%. With methysergide, geniohyoid data was unavailable but sternohyoid activity was similarly suppressed as with ritanserin. Diaphragmatic muscle activity was reduced, but only slightly (5-17%) by ritanserin and more substantially (33-60%) by methysergide. Both reduced oxyhemoglobing saturation, from basline 92% to 88% by ritanserin and from baseline 90% to 86% by methysergide. The authors noted that such desaturations do not normally occur in waking animals. With ritanserin, there were large reductions in airway area during inspiration but no changes during expiration; in fact, without ritanserin airway area increased markedly during inspiration, whereas after ritanserin area decreased markedly during inspiration, so that airway dynamics were drastically altered. Similar data was unavailable for methysergide.
The authors concluded they had shown the two serotonin antagonists to produce compromise of upper airway function in the waking English bulldog, with marked suppression of upper airway dilator muscle activity and less suppression of diaphram activity, the suppressions of motor activity coinciding with oxyhemoglobin desaturations. As to their theory of the neuroanatomical basis for these effects, they noted that the systemic administration of the drugs made it impossible to rule out effects of neurons in other parts of the brain other than the caudate raphe nucleus. Further clarification of this would require local injections. They noted their inability to show a dose-dependency of their effects but felt this might be attributed to a number of factors, such as the small numbers of animals studied, the use of behaving animals, the variability in severity of disease, and perhaps selection of the wrong dosage range to demonstrate this relationship. In any case, they had demonstrated that serotonin antagonism reduced airway dilator activity and reproduced changes consistent with obstructive sleep apnea in the waking animals.
With regard to clinical implications, they noted other research in human suggesting that L-tryptophan, a precursor of serotonin, and fluoxetine, a serotonergic antidepressant, reduced the number of respiratory events during sleep in some sleep apneics, and suggested that further research might lead to more selective serotonin enhancers that would prove more effective in increasing the activity of upper airway motoneurons during sleep, leading to a pharmacological treatment for sleep apnea. They considered that CPAP, while effective, is cumbersome and poorly tolerated by many, so that a pharmacotherapy would be preferable.
Out of a general reluctance to leap from early animal studies to clinical implications from human beings, and furthermore from a study of drugs unlikely to be used with patients in any case to drugs with hypothetically opposite and therapeutic effects, I was debating whether to review this study here at all. What decided me to do it was a report from one of our number that a very recent study, possibly not yet published in more than abstract form, had shown two drugs often considered "serotonergic" had been shown helpful in English bulldogs for improving sleep efficiency and reducing arousals, AHI, and desaturations in a somewhat dose-dependent manner. These two drugs were said to be L-tryptophan, no longer available on the world market, and trazodone (Desyrel) which is widely available and used for improving sleep in depressed patients with insomnia or sleep disturbance as a side effect of the popular serotonin reuptake inhibitors such as fluoxetine (Prozac). Moreover, trazodone has a close relative, nefazodone (Serzone) which has been shown superior to fluoxetine in improving sleep.
At the least, there has so far been no clinical indication of trazodone aggravating sleep apnea, and its widespread use indicates the likelihood that it has been used, at least inadvertently, in many depressed patients with unrecognized sleep apnea. Many psychiatrists have come to prefer trazodone to the conventional benzodiazepine sleeping pills (like temazepam/Restoril and triazolam/Halcion) for its apparently lower liability to tolerance and dependence and possibly stronger sleep-inducing effects. It would be good to see some controlled research utilizing sleep polysomnography in sleep apneics given such sedative antidepressants, if only to reassure us of their safety, with the possibly added benefit of improvement in the respiratory problem. Meanwhile, the case for serotonergic drugs as an alternative to CPAP is far from proven: it is not even clear that the predominant effect of trazodone, which has a variety of mixed effects, is serotonergic, and it is clear that more purely serotonergic antidepressants like fluoxetine often have adverse effects on sleep, if not yet year whether they have any effect on obstructive respiratory events. The role of drugs, like that of surgery, is less promising as an alternative first line treatment to CPAP than as a possible alternative when CPAP appropriately and consistently used yields only partial therapeutic effects on sleep apnea or sleep disturbance from other causes in sleep apneics.
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