Am. J. Respir. Crit. Care Med., Volume 160, Number 5, November 1999, 1659-1667

The Effects of Trazodone with L-Tryptophan on Sleep-disordered Breathing in the English Bulldog

SIGRID C. VEASEY, POLINA FENIK, KAREN PANCKERI, ALLAN I. PACK, and JOAN C. HENDRICKS

Center for Sleep and Respiratory Neurobiology; Division of Pulmonary and Critical Care, Department of Medicine, School of Medicine; Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder, for which there are no universally effective pharmacotherapeutics. We hypothesized that in OSAHS, excitatory serotoninergic influences are important for maintaining patency of the upper airway in waking, and that in sleep, reduced serotoninergic drive plays a significant role in upper airway collapse and OSAHS. The previously reported small responses in humans with OSAHS to serotoninergics may relate, in part, to study design and the drugs/doses selected. We therefore performed multitrials/dose, multidose, randomized sleep studies testing the effectiveness of a combination of serotoninergics, trazodone, and L-tryptophan, in our animal model of OSAHS, the English bulldog. Trazodone/L-tryptophan caused dose-dependent reductions in respiratory events in non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS). During NREMS, the respiratory disturbance index (RDI) ± standard error was 6.3 ± 1.4 events/h (placebo) and 0.9 ± 0.3 (highest dose), p < 0.01. During REMS, the RDI was 31.4 ± 6.1 events/h (placebo) and 11.5 ± 4.3 (highest dose), p = 0.002. Trazodone/ L-tryptophan dose-dependently reduced sleep fragmentation, p = 0.03, increased sleep efficiency, p = 0.005, enhanced slow-wave sleep, p = 0.0004, and minimized sleep-related suppression of upper airway dilator activity, p < 0.02. Trazodone with L-tryptophan can treat sleep-disordered breathing (SDB) in an animal model of OSAHS; the effectiveness of this therapy may be related to increased upper airway dilator activity in sleep and/or enhanced slow-wave sleep. Veasey SC, Fenik P, Panckeri K, Pack AI, Hendricks JC. The effects of trazodone with L-tryptophan on sleep-disordered breathing in the English bulldog.

This article has been cited by other articles:

				G. Jayaraman, H. Sharafkhaneh, M. Hirshkowitz, and A. Sharafkhaneh Review: Pharmacotherapy of obstructive sleep apnea Therapeutic Advances in Respiratory Disease, December 1, 2008; 2(6): 375 - 386. [Abstract] [PDF]

				R. C. Heinzer, D. P. White, A. S. Jordan, Y. L. Lo, L. Dover, K. Stevenson, and A. Malhotra Trazodone increases arousal threshold in obstructive sleep apnoea Eur. Respir. J., June 1, 2008; 31(6): 1308 - 1312. [Abstract] [Full Text] [PDF]

				E. Chan, H. W. Steenland, H. Liu, and R. L. Horner Endogenous Excitatory Drive Modulating Respiratory Muscle Activity across Sleep-Wake States Am. J. Respir. Crit. Care Med., December 1, 2006; 174(11): 1264 - 1273. [Abstract] [Full Text] [PDF]

				C. R. A. Aoki, H. Liu, G. P. Downey, J. Mitchell, and R. L. Horner Cyclic Nucleotides Modulate Genioglossus and Hypoglossal Responses to Excitatory Inputs in Rats Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 555 - 565. [Abstract] [Full Text] [PDF]

				S. Sood, J. L. Morrison, H. Liu, and R. L. Horner Role of Endogenous Serotonin in Modulating Genioglossus Muscle Activity in Awake and Sleeping Rats Am. J. Respir. Crit. Care Med., November 15, 2005; 172(10): 1338 - 1347. [Abstract] [Full Text] [PDF]

				V. B. Fenik, R. O. Davies, and L. Kubin REM Sleep-like Atonia of Hypoglossal (XII) Motoneurons Is Caused by Loss of Noradrenergic and Serotonergic Inputs Am. J. Respir. Crit. Care Med., November 15, 2005; 172(10): 1322 - 1330. [Abstract] [Full Text] [PDF]

				T. Ogasa, A. D. Ray, C. P. Michlin, G. A. Farkas, B. J. B. Grant, and U. J. Magalang Systemic Administration of Serotonin 2A/2C Agonist Improves Upper Airway Stability in Zucker Rats Am. J. Respir. Crit. Care Med., October 1, 2004; 170(7): 804 - 810. [Abstract] [Full Text] [PDF]

				T. Saaresranta and O. Polo Hormones and Breathing Chest, December 1, 2002; 122(6): 2165 - 2182. [Abstract] [Full Text] [PDF]

				F. Series and G. Ethier Site of phrenic nerve stimulation-induced upper airway collapse: influence of expiratory time J Appl Physiol, February 1, 2002; 92(2): 665 - 671. [Abstract] [Full Text] [PDF]

				F. Series and I. Marc Functional Genomics of Sleep and Circadian Rhythm: Selected Contribution: Influence of genioglossus tonic activity on upper airway dynamics assessed by phrenic nerve stimulation J Appl Physiol, January 1, 2002; 92(1): 418 - 423. [Abstract] [Full Text] [PDF]

				A. Jelev, S. Sood, H. Liu, P. Nolan, and R. L Horner Microdialysis perfusion of 5-HT into hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep-wake states in rats J. Physiol., April 15, 2001; 532(2): 467 - 481. [Abstract] [Full Text] [PDF]

				S. C. Veasey Serotonin . Culprit or Promising Therapy for Obstructive Sleep Apnea? Am. J. Respir. Crit. Care Med., April 1, 2001; 163(5): 1045 - 1047. [Full Text]