The effects of fluoxetine (FLU) and its active metabolite, norfluoxetine (NFLU), on the polysomnogram (PSG) of nine depressed outpatients (eight with major depression; one with bipolar II, depressed phase disorder) were investigated by contrasting PSG values prior to treatment and during administration of FLU. The PSG changes were correlated with daily dose, cumulative dosage, single serum concentrations, and the total area under the serum concentration curve (AUC) of both FLU and NFLU.KEY WORDS: Fluoxetine; Norfluoxetine; Polysomnography; Serotonin; Depression Fluoxetine (FLU)-a potent, specifIc, serotonin reup take inhibitor-is an effective treatment for major depression (for a review, see Depression Guideline Panel, 1993). Serotonin affects the regulation of the sleep-wake cycle. It plays a role in the induction and maintenance of sleep as well as the character of sleep stage macro architecture and rapid-eye-movement (REM) sleep expression Oouvet et al. 1989).Fluoxetine reportedly causes a shift toward lighter Fluoxetine clearly increased both stage 1 sleep time and rapid-eye-movement (REM) latency and decreased both percent REM and REM density. With a few exceptions, the cumulative dosage of FLU and the AUC of FLU and NFLU were better predictors of the changes in awake and movement time in the PSG than single-sample concentrations of FLU and NFLU taken at the time of PSG assessment. fNeuropsychopharmacology 10: 85-91, 1994J sleep that is reflected in increases in sleep latency and percentage of non-REM stage 1 sleep and decreases in total sleep time, sleep efficiency, and percentage of non REM stages 3 and 4 sleep (Nicholson and Pascoe 1986;Pastel and Fernstrom 1987;Kerkhofs et al. 1990;Keck et al. 1991;Keck and McElroy 1992). The duration of REM sleep and REM latency, as well as REM density, may also be affected by FLU (Nicholson and Pascoe 1988;von Bardeleben et al. 1989;Nicholson et al. 1989; Bakalian and Fernstrom 1990;Hanzel et al. 1991;Saletu et al. 1991). These effects likely depend upon both the dose and duration of FLU treatment.Changes in polysomnogram (PSG) measures as sociated with chronic FLU treatment in depressed sub jects have been incompletely studied (Schenck et al. 1992). Relationships among PSG measures and serum concentrations of FLU and its active metabolite norflu oxetine (NFLU) have not been previously reported in depressed patients. This pilot study evaluated the effect of FLU and NFLU on PSG measures in a group of medication-responsive depressed outpatients.
A procedure has been developed for measuring fluoxetine and its desmethyl metabolite, norfluoxetine, in serum by reversed-phase high-performance liquid chromatography (HPLC), with ultraviolet detection at 226 nm. Fluoxetine and norfluoxetine are isolated from serum by liquid-liquid extraction. They are then separated by HPLC and quantified, with reduced haloperidol as the internal standard. Fluoxetine, norfluoxetine, and the reduced haloperidol are separated from all interfering peaks in about 15 min. The standard curve is linear (r = 1.000) for both fluoxetine and norfluoxetine concentrations over the range of 25 to 800 micrograms/L. Between-run CVs for 60 and 200 micrograms/L controls (n = 8) were 6.8 and 4.1% for fluoxetine, and 8.8 and 6.2% for norfluoxetine, respectively. In a study of 24 patients with depression who were being treated with 20-60 mg of fluoxetine per day, fluoxetine and norfluoxetine concentrations in serum, measured during the last three weeks of treatment, were 47-469 micrograms/L and 52-446 micrograms/L, respectively.
The sleep macroarchitecture of 10 outpatients with obsessive-compulsive disorder (OCD) was compared to a group of symptomatic, unmedicated outpatients with nonpsychotic major depressive disorder (MOO) (n = 10). No group main effects were observed. Gender by group interactions were observed on the amount of wakefilness and total sleep period. Male patients with M D D had the highest amount of wakefilness, whereas female patients with OCD showed the least amount of wakefilness. Of the REM sleep parameters, only the duration of the individual REM periods showed between-group dsfferences, interacting with gender. Gender main effects were also obtained on the amount of Stage 1 sleep, which was lower among females. R E M latency did not diflerentiate the groups. These findings suggest that selected sleep EEG parameters may diflerentiate patients with M D D f r o m those with OCD, but that these effects are moderated by gender. Depression 2:297-302 (1 99411 995). 0 1995 Wiley-Liss, Znc.
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