TRAZODONE ENHANCES SLEEP IN SUBJECTIVE QUALITY BUT NOT IN OBJECTIVE DURATION

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1 Br. J. clin. Pharmnac. (1983), 16, TRAZODONE ENHANCES SLEEP IN SUBJECTIVE QUALITY BUT NOT IN OBJECTIVE DURATION I. MONTGOMERY*, I. OSWALD, K. MORGAN & KIRSTINE ADAM University Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh EH10 5HF 1 Nine volunteer poor sleepers, of mean age 61 years, took trazodone 150 mg nightly for 3 weeks, preceded by 2 weeks and followed by 1 week of matching blanks, in order to examine the effects of electrophysiologically-recorded and subjectively-rated sleep. The second of the initial weeks of matching blanks served as a baseline week. 2 In the subjective ratings, sleep improved in quality on trazodone, significantly so in the first and second weeks of intake, though with significant rebound insomnia on the second withdrawal night. 3 Trazodone halved the frequency of arousals interrupting sleep, and it reduced the time spent in stage 1 (drowsiness). It increased the duration of slow-wave sleep (stages 3 + 4), with a negative rebound following withdrawal. It reduced the time spent in REM sleep, with a rebound above baseline levels after withdrawal. 4 Trazodone did not change total sleep duration, nor the time required to fall asleep. 5 The effects of trazodone were sustained or became enhanced during the period of intake. They persisted for over 24 h after the last dose, and rebound effects were maximal on the second withdrawal night. Keywords trazodone sleep rebound effects Introduction Trazodone is a modem antidepressant drug, a triazolopyridine derivative, the pharmacology of which has been reviewed by Al-Yassiri et al. (1981), and it has been reported to cause drowsiness (Kamiol et al., 1976; Brogden et al., 1981). Since the majority of depressed patients are anxious and have difficulty in sleeping, the present study set out to explore possible hypnotic effects of trazodone 150 mg nightly. The recommended starting dosage for clinical use is mg daily and, in common with other antidepressants, it is recommended for bedtime intake. In clinical practice antidepressants have to be taken for several weeks for full benefit to be achieved and trazodone 150 mg daily is held to be no exception (Mann et al., 1980; Brogden et al., 1981). The present study therefore provided for 3 weeks of administration, so that time-related effects might emerge. It was of interest to see whether trazodone would alter the subjective judgement of sleep and change objective measures of sleep, such as total sleep duration, the frequency of arousals and the structure of sleep in terms of conventional stages, and also to consider withdrawal effects. *Present address: Department of Psychology, University of Tasmania, G.P.O. Box 252C, Hobart, Australia Methods Subjects Nine volunteers, selected because they believed themselves to be poor sleepers, seven women and two men, aged (mean 61 years), took part. They had taken no CNS drugs in the preceding 2 months, they agreed to abstain from alcohol and other CNS drugs during the study, they gave their informed consent, they took part with the agreement of their family doctors, and with the approval of the Ethics Committee of the Royal Edinburgh Hospital. Experimental design Subjects attended the sleep laboratory on a total of 14 nights each, spread over 6 weeks. During the first 2 weeks blank (placebo) capsules were taken every night at bedtime, whether at home or in the laboratory. In the next 3 weeks matching capsules of trazodone 50 mg were taken, three capsules nightly at bedtime, while in the final week blanks were again taken each night. Each subject, on every morning throughout the study, about 20 min after rising, completed visual analogue 100 mm scales to make a subjective rating of 1983 Blackwell Scientific Publications

2 140 I. MONTGOMERY ETA L. the quality of the previous night's sleep (worst possible-best ever) and a rating of how alert and vigilant he or she felt (marvellously alert and energeticawfully sleepy and lack-lustre). In the first week of blanks there were 2 nights at the sleep laboratory for adaptation and in the second week 2 nights for the recording of baseline values. The first and third nights of the subsequent week were recorded to give 'early drug' data. At the end of the fourth week there was a further adaptation night and in the fifth week (the third trazodone week) the 19th and 21st nights on the drug were recorded to give 'late drug' data. In the final week of matching blanks, the first, second third, fifth and seventh nights were recorded. Electrophysiological recording ofsleep On all nights the electroencephalogram (EEG), eye movements and submental muscle tone (EMG) were recorded. Lights-out was at approximately h and the mean total recording time was 510 min each night, being always the same for any one subject to within the nearest 5 min. All sleep records were coded, mixed in order and categorized 'blind' for the different stages of sleep and wakefulness. The code was then broken and the data analyzed. Statistical analysis In the case of the visual analogue scales the number of mm from the left-hand end of the line to the subject's mark was used. Because each subject creates his own scale and range, the data were converted to deviations from the individual's own baseline mean, expressed as a percentage of his baseline standard deviation. Weekly means for each subject were then used, ignoring the initial adaptation week. In the case of the electrophysiological data, the mean for each subject on the two baseline nights was used, the mean of the two early drug nights, the mean of the two late drug nights, and the five individual withdrawal nights. A 1 x 8 analysis of variance with repeated measures across the nine subjects was used to test the overall differences among the sets of data. Where the null hypothesis could be rejected, t-tests for paired observations, with 8 degrees of freedom, were used to compare the different periods. All P values quoted are for the two-tailed level of significance. However, values for sleep onset latencies and for REM sleep latencies are not normally distributed. Friedman's analysis of variance by ranks was used to test the overall significance of the differences for REM sleep latency, and thereafter the Wilcoxon matched pairs signed ranks test was used to compare the different periods. The sleep onset latency data were first transformed into natural logarithms and analysis of variance and t-tests used thereafter (Johns, 1977). In some of the analyses given below, the total duration of sleep is held constant by employing the first 4 h of accumulated sleep. This was because all subjects on all nights achieved a total of at least 4 h of total sleep, though not 5 h. Results Table 1 shows mean values for the most important sleep data and Table 2 shows values for the first 4 h of sleep, and in each case analyses of variance are indicated. It may first be noted that no significant effects emerged in the case of either total sleep duration or sleep efficiency (the proportion of lights-out time actually spent in sleep). Sleep onset latency There were significant variations in the time taken to fall asleep, arising from significant reduction, compared with baseline, on withdrawal nights 3 (t = 2.38, P < 0.05) and 5 (t = 3.04, P < 0.05). REM latency The number of minutes of sleep between first onset of stage 2 sleep and the first appearance of REM sleep (any wakefulness being excluded) was significantly affected. Trazodone intake was associated with nonsignificant increase, and withdrawal with a decrease below baseline that reached significance on withdrawal night 5 (t = 2.073, P < 0.05). Wakefulness afterfirst sleep onset There was some reduction of wakefulness during drug intake and a tendency to enhance wakefulness on the second and third withdrawal nights. During the late drug period the reduction of wakefulness was significant compared with baseline (t = 2.84, P < 0.05). Considering only wakefulness intervening during the first 4 h of accumulated sleep, the same trend was apparent. Owing to evident skew, a non-parametric analysis of variance was performed; also non-significant (X2 = 9.315, d.f. = 7, P> 0.2). Distribution ofsleep stages Stage 1 sleep and REM sleep were reduced by trazodone, while stages were increased. Compared with baseline, total stage 1 was reduced during the early drug period (t = 4.64, P < 0.005) and the late drug period (t = 6.31, P < 0.001). Considering the first 4 h of sleep only, these reductions again were significant (t = 3.93, P < 0.01 and t = 4.48, P < 0.01). There were no significant differences between early drug and late drug. The significant reduction of stage

3 Table 1 Trazodone: principal features of sleep (means ± s.d.) Total sleep time (min) Sleep onset latency, lo& (min) REM latency (min) Total wake after sleep onset (min) Total stage 1 (min) Total stage 2 (min) Total stages (min) Total REM sleep (min) % REM sleep Base- Early Late line drug drug ± ± ± ± ± ± ± ±15.4 ± ± ± ± ± ± ± ± ±25.8 ± ± ± ± ±8.3 Withdrawal TRAZODONE AND SLEEP 141 Analysis of variance 5 7 d.f. = 7, ± ± F= 1.15 NS F= 3.73 P < )er = 16.5 ±+17.5 ±53.1 ±22.1 ± P = 0.02 (d.f. = 7) ± F= 2.24 P < ± F= 9.56 P< F= 2.4 P < ± ± ± ± ±40.3 F= 6.10 P < ±25.6 ± ±30.4 F= 2.45 P < ± ± ± ± ±5.7 F= 6.02 P < persisted into withdrawal night 1 (first 4 h, t = 2.47, P<O.O5). REM sleep also was reduced by trazodone, as was most apparent as a percentage of total sleep: for the early drug week, t = 3.82, P < 0.005, and for the late drug week, t = 4.81, P < These effects were present in the min of REM sleep in the first 4 h of sleep (t = 2.54, P < 0.05 and t = 2.55, P < 0.05). REM sleep was enhanced during withdrawal compared with baseline, significantly so on withdrawal night 5: % REM, t = 3.98, P < 0.005, and min in first 4 h, t = 2.45, P < The duration of stages (slow wave sleep) in the whole night was increased by trazodone (Figure 1) during early drug (t = 2.70, P < 0.05) and during late drug (t = 3.87, P < 0.005). The increase was significantly greater during the late than the early drug nights (t = 2.76, P < 0.05). Considering only the first 4 h of sleep, the same effects emerged: for early drug, t = 2.58, P < 0.05, late drug, t = 3.61, P < 0.01 and for early vs late, t = 2.28, P < On withdrawal there was a rebound reduction below baseline levels, significant on the second withdrawal night for the whole night, t = 2.48, P < 0.05, and for the first 4 h of sleep, t = 2.58, P < Stage 2 sleep was not significantly altered with respect to baseline, though there was a trend to increase with trazodone and decrease on withdrawal, the significance on analysis Table 2 Trazodone: features within the first total 4 h of accumulated sleep Base- Early Late line drug drug Withdrawal Analysis of variance 5 7 d.f. = 7,56 Intervening wakeful F= 1.50 ness (min) ± NS Stage 1 (min) F= 7.23 ± ±+15.1 ±+13.2 ±+13.8 ±+15.7 ±15.1 P < Stages (min) F = 6.43 ±26.5 ±29.2 ± ±31.5 ±33.7 P < REM sleep (min) F = 6.34 ±12.6 ±+14.5 ± ±13.3 ±+12.5 o10.0 ±+15.1 ±+12.6 P < Number of shifts to F= 7.38 awake + shifts to stage 1 +±14.7 ±4.1 ±5.3 +± ± 15.1 ±15.2 P < 0.001

4 142 I. MONTGOMERY ETA L. -C 0) CD rzdn eln Wtdaa 0) cm 30- Baseline Trazodone Withdrawal placebos 150 mg nightly for 3 weeks placebos Figure 1 Trazodone increases the duration of slow wave sleep. Rebound on second withdrawal night. of variance being attnbutable to the difference between early drug and withdrawal night 5. The frequency with which sleep was broken by arousals to stage 1 or awake from any other stage of sleep was reduced by trazodone. Holding sleep duration constant at 4 h, these arousals were roughly halved compared with baseline (early drug, t = 2.63, P < 0.05; late drug, t = 3.02, P < 0.01). An apparent withdrawal rebound, with greater frequency of arousals, did not attain significance. Subjective ratings Trazodone improved the subjective quality of sleep (Figure 2). The improvement was apparent during all 3 drug weeks, though reached significance only during the first and second. On analysis of variance, F = 5.23, d.f. = 4,32, P < Comparing the baseline week with the first week on trazodone, t 2.56, P < 0.05; for the second trazodone week, t 3.82, P < 0.01; for the third week, t = 1.81, NS. A further analysis of variance, but with the withdrawal week treated as seven nights, gave F= 3.30, d.f. = 10,80, P < and, as Figure 2 suggests, withdrawal night 2 was found to be associated with significantly impaired quality of sleep compared with the baseline week (t = 2.46, P < 0.05). The drug was associated with a tendency to impaired morning vigilance, but no significant effects emerged (F= 2.54, d.f. = 4,32, P <0.06). Discussion The middle-aged subjects were selected as poor sleepers, and Table 2 confirms this, showing, for example, that on average over half an hour of wakefulness intruded into their first 4 h of sleep. In that trazodone improved the subjective quality of sleep and halved the frequency of arousals it must be considered to be a drug that has hypnotic activity. Although there were trends to lesser wakefulness, these were not consistently significant and sleep was not made longer. Among the objective measures, it was found that trazodone reduced REM sleep, as is true of other antidepressant drugs, such as tricyclics Better Mean deviation from each individual's baseline mean (% of baseline s.d.) U I I mean Figure 2 Worse Baseline 1- Trazodone 150 mg nightly -- placebos for 3 weeks Withdrawal placebos Trazodone improves subjective quality of sleep. Rebound on second withdrawal night.

5 TRAZODONE AND SLEEP 143 (Dunleavy et al., 1972; Gillin et al., 1978), the monoamine oxidase inhibitors (Dunleavy & Oswald, 1973), viloxazine (Brezinova et al., 1977) or mianserin (Morgan et al., 1980). What was unusual was trazodone's effect in increasing SWS, which has rarely been reported as an effect of any drug though, among drugs used for mood disorders, it has been found for lithium (Chernick & Mendels, 1973; Kupfer et al., 1974). We have recently also described such an action in the case of an investigative drug having anti-5-ht properties (Oswald et al., 1982a), but for which there was rapid tolerance in the case of the SWS effects. Trazodone also is reported to have both central and peripheral anti-5-ht properties (Al- Yassiri et al., 1981). In our study trazodone has an effect on SWS that became significantly greater after 2 weeks or more of continued intake, perhaps paralleling the slow brain change that must be hypothesized to underly the characteristically delayed beneficial effects on the mood of depressed patients (Oswald et al., 1972). Owing to the fact that the significant reduction in stage 1 (drowsiness) caused by trazodone was still present on the first withdrawal night, and because most measured withdrawal effects peaked on the second withdrawal night, it must be supposed that significant amounts of the drug, or some active metabolite will persist in the human brain for over 24 h after modest clinical dosage. The significant improvement in subjective quality of sleep during drug intake, followed by insomnia on the second withdrawal night, resembles what is found with intake and then withdrawal of, for example, lormetazepam 2 mg (Oswald et al., 1982b), an hypnotic drug with a plasma half-life of 10 h (Humpel et al., 1979). Our observations thus suggest a rather longer persistence of active substance in middle-aged subjects than might be inferred from various studies of plasma half-life reviewed by Al Yassiri et al. (1981). The shorter sleep latency on the third and fifth withdrawal nights after trazodone may have been a manifestation of increased adaptation to the laboratory, owing to more frequent recordings during this phase of the study. Finally, it should be mentioned that there are objective correlates between the EEG stages and sleep as a deeper and presumptively more restorative state. It is SWS that has first priority for recovery after sleep deprivation (Berger & Oswald, 1962), SWS has been concluded to be 'worth more' (Dement & Greenberg, 1966), it is associated with the lowest degree of nocturnal responsiveness (Williams et al., 1966), it is specifically associated with the large nocturnal growth hormone secretion (Sassin et al., 1969), it is coupled with the most profound degree of rest as indicated by the lowest whole body oxygen consumption (Brebbia & Altshuler, 1968; Haskell et al., 1981) and is coupled with the lowest level of blood pressure (Coccagna et al., 1971). It may be, of -course, that trazodone merely acts upon some final generating mechanism of EEG waves, but the fact that it is associated with subjectively improved quality of sleep allows the hypothesis that the increased duration of slow-wave sleep that we have observed is correlated with a more profound degree of rest and restoration. 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