The Acute Effects of the Noradrenaline Reuptake Inhibitor Org 4428 on EEG Sleep in Healthy Volunteers

Abstract

Drug-induced improvement of depression may be mediated by changes in sleep physiology. In earlier studies on sleep EEG changes during treatment with antidepressants in depressed patients it could not be excluded that sleep disruptions and changes in the amount and distribution of REM sleep play a role in the changes in the sleep EEG. Therefore knowledge of the effects of antidepressants on the sleep EEG in healthy subjects with non-disturbed baseline sleep is necessary. In a three-way cross-over study in 12 healthy volunteers two single doses of Org 4428 (a highly specific noradrenaline reuptake inhibitor), 25 and 100 mg, were compared with placebo. Sleep EEGs were visually analysed and EEG power of non-REM sleep was measured. The results indicate that sole noradrenaline reuptake inhibiting activity is a potent mechanism to affect sleep polygraphic variables in an antidepressant-like way, i.e. REM sleep suppression and lengthening of REM latency. Despite the increase in the duration of non-REM sleep, i.e. stage 2, no significant changes in EEG power in the range 1–15 Hz were found. Therefore, the acute REM sleep suppression of Org 4428 did not result in a simultaneous reduction of EEG power during non-REM sleep. To date, these and earlier results indicate that most drugs with antidepressant properties affect REM sleep variables consistently, whereas their effect on both sleep polygraphic and EEG power variables in non-REM sleep is unpredictable.

Comparative effects of duloxetine and desipramine on sleep EEG in healthy subjects

“…The effects upon REM sleep produced by desipramine, a TCA with predominantly NE reuptake inhibition, confirm earlier clinical observations reported for this agent (Shipley et al 1985;Kupfer et al 1991) as well as other selective NE reuptake inhibitors such as viloxazine, maprotiline, Org 4428, and reboxetine (Brezinova et al 1977;Nicholson and Pascoe 1986;Van Bemmel et al 1999;Farina et al 2002). The results demonstrate that sole NE reuptake inhibition, achieved by a pharmacological intervention, has an effect on sleep polygraphic variables similar to that of most antidepressant medications, i.e.…”

Effects of Rapid Tryptophan Depletion on Sleep Electroencephalogram and Mood in Subjects with Partially Remitted Depression on Bupropion

“…Support for this comes from studies of NE reuptake inhibitors on sleep. Desipramine, Org 4428, and nortriptyline, for example, all significantly decrease REM time and REM% (Hishikawa et al 1965;Ross et al 1995;Baumann et al 1983;Dunleavy et al 1972;van Bemmel et al 1999;Buysse et al 1996;Reynolds et al 1997;Taylor et al 1999). Perhaps bupropion's main mechanism of action is not NE reuptake inhibition but some other unidentified NE or DA mechanism.…”

Changes of Sleep Architecture, Spectral Composition of Sleep EEG, the Nocturnal Secretion of Cortisol, ACTH, GH, Prolactin, Melatonin, Ghrelin, and Leptin, and the DEX-CRH Test in Depressed Patients during Treatment with Mirtazapine

“…The involvement of adaptational mechanisms is further supported by a study with Org4428, a highly specific norepinephrine reuptake inhibitor. An acute administration of Org4428 does not result in EEG spectrum changes in the frequency range 1-15 Hz, despite strong effects on sleep architecture including REM sleep suppression and increase of stage 2 (Van Bemmel et al, 1999). Also of interest is an earlier study with trazodone, acting as SSRI 5-HT2 antagonist, alpha 1 and weak alpha 2 antagonist, with an influence on the histaminergic system.…”