MOOD VARIABILITY AND SLEEP DEPRIVATION EFFECT AS PREDICTORS OF THERAPEUTIC RESPONSE IN DEPRESSION

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1 MOOD VARIABILITY AND SLEEP DEPRIVATION EFFECT AS PREDICTORS OF THERAPEUTIC RESPONSE IN DEPRESSION Gordijn, M.C.M., Beersma, D.G.M., Bouhuys, A.L., Van den Hoofdakker, R.H. Dept. of Biological Psychiatry, University Clinic, P.O. Box , 9700 RB Groningen, The Netherlands INTRODUCTION The variability of diurnal mood variations (DVs) in depressed patients correlates positively with the therapeutic effect of total sleep deprivation (TSD) (Gordijn et al., 1994). We proposed that high variability of DVs reflects a patient s vulnerability to external factors, which might explain the effects of TSD or other antidepressive treatments. A relationship between sleep deprivation response and therapeutic response to treatment with antidepressants has been demonstrated in two studies (Wirz- Justice et al., 1979; Fähndrich, 1983). Wirz-Justice et al. (1979) reported that of 34 sleep deprivation responders, 24 improved after subsequent tricyclic antidepressant treatment. Fähndrich (1983) stated that responders to sleep deprivation have a good chance of being successfully treated with clomipramine whereas non-responders to sleep deprivation can more likely be successfully treated with maprotiline. In the latter study also the presence of DVs during treatment predicted an antidepressant response. Purpose of the present study was to analyse the relationships between diurnal mood variability, the therapeutic effect of sleep deprivation and outcome after a 6-weeks period of antidepressive therapy. METHODS Our database consists of selfratings of mood on an adjective mood scale (AMS, Von Zerssen, 1986) at 9 a.m. and 10 p.m. during a 6 weeks period of antidepressive therapy. The ratings were done by 81 depressed in-patients (57 women and 24 men). So-called Hamilton ratings (HRSD 21-items, Hamilton, 1967) were present at the beginning (T1) and end of the treatment period (T2). Drug treatment consisted of antidepressants (n=79), predominantly clomipramine (n=62). The antidepressants were sometimes combined with neuroleptics (n=24) and/or lithium (n=23). One subject received neither antidepressants nor neuroleptics, nor lithium and one subject received lithium as monotherapy. Each patient was subjected to at least one total sleep deprivation within the first 14 days after T1. For each individual, we calculated (1) the average sleep deprivation effect over the total number of available sleep deprivation nights (range 1-4) within this period, (2) the average difference between mood on the day after sleep deprivation and mood on the day after recovery-sleep and (3) the average difference in mood on the day before a normal night of sleep and the day after. Additionally, we calculated (4) the average amplitude of the DVs and (5) the variability of the DVs (i.e. the standard deviation of the DVs) on the first 14 days after T1, excluding the day before and after TSD. 41

2 Correlations between the sleep deprivation effect, the effect of recovery sleep, diurnal mood variation and the variability in DV with the severity of depression (HRSD) at T2 were performed to analyse their relationships with outcome after 6 weeks. In the analysis the severity of depression (HRSD) at T1 was controlled for. Multiple regression analysis (stepwise) was performed with the variables that showed significant correlations in order to examine whether they predict therapy outcome independently. RESULTS On average, mood improved 3.7±0.9 (se) AMS points after TSD relative to the day before TSD (F(1,80)=17.16, p<0.001). After one night of recovery-sleep average mood worsened on average 1.3 ± 1.0 AMS points relative to the day after sleep deprivation (F(1,80)=1.72, n.s.), (figure 1a). The average difference between mood on the day before a normal night of sleep and the day after was 0.6 ±0.3 (figure 1b, n=76). Five patients were excluded because there were no days before and after normal sleep left after exclusion of the days before and after TSDs and recovery-sleep. Figure 1: a. The average selfratings of mood at 9:00 and 22:00 h before total sleep deprivation, after total sleep deprivation and after one night of recovery-sleep. Values were obtained during the first 14 days of treatment, (81 depressed patients, range of sleep deprivations per individual 1-4). b. The average selfratings of mood at 9:00 and 22:00 h on two consecutive days, within the first 14 days of treatment, with a normal night of sleep in between. Days prior to and following sleep deprivation, as well as days following recovery sleep were excluded, (76 depressed patients, range of two consecutive days per individual 1-5). 42

3 The average sleep deprivation effect is significantly different from the average mood difference between two days with a normal night of sleep in between (F(1,75)=8.67, p<0.005). The relapse in mood after recovery-sleep is not significantly different from the mood change over a night of normal sleep (F(1,75)=1.38, n.s.). The difference between mood on the day after recovery sleep and the day prior to sleep deprivation (2.4 AMS points) is even significantly different from the average change in mood ratings over three days with two normal sleep nights in between (0.2±0.5, n=60 due to missing days, F(1,59)=8.9, p<0.005). The average difference between the AMS rating in the morning and the AMS rating in the evening (the amplitude of the DV) was 2.1±0.6 (F(1,80)=14.62, p<0.001) and the standard deviation (variability of DV) was 5.5±0.6. Baseline severity of depression (HRSD at T1) was 25.4 ± 5.3 (sd). The HRSD at T2 was 19.1 ± 9.0. Partial correlations between the average DV-amplitude, the variability of DV, the TSD effect and the recovery-sleep effect in the first 14 days, with the HRSD rating at T2, controlled for the HRSD rating at T1, revealed significant correlations for variability of DV (r=-0.26, p<.05), TSD effect (r=-0.36, p<.001) and for the effect of recovery-sleep (r=.29, p<.01) but not for the average DV-amplitude (r=0.008, p=.94). Thus, a large variability in diurnal mood variations, a beneficial sleep deprivation effect and a small relapse after recovery-sleep in the first 14 days were correlated with a relatively low depression score after a 6 weeks period with antidepressive therapy. Multiple regression analysis was performed with HRSD at T1 forced into the equation as block 1 and variability of DV, sleep deprivation effect and recovery-sleep effect as block 2, with HRSD at T2 as the predicted variable. The results are presented in table 1. A high baseline severity of depression (HRSD T1) predicted a high severity of depression at T2. In other words, patients who were severely depressed at the start of the 6 weeks period had a high chance to be severely depressed after 6 weeks. In the second step, only the sleep deprivation effect contributed significantly to the equation: a beneficial sleep-deprivation response predicted low depression scores. Table 1: Prediction of depression outcome (HRSD T2) after 6 weeks, results of multiple regression analysis (stepwise). Predictor ß t p F(2,78) adjusted R 2 p Step 1 baseline HRSD (T1): Step 2 sleep deprivation effect: Variables not in the equation: variability of DV and recovery-sleep effect (p>0.1) 43

4 CONCLUSIONS The first conclusion from this study on sleep deprivation effects in a large group of depressed inpatients is that sleep deprivation has on average a significant mood improving effect. The sleep deprivation effect was significantly different from normal day to day mood changes. The relapse in mood after one night of recovery-sleep was not significant, and even more importantly, the average mood change over the recovery-night was not significantly different from the average change in mood over a normal night of sleep. Mood stayed improved on the day after recovery sleep compared to mood on the day prior to sleep deprivation and this was significantly different from the course of mood over three days with two normal sleep nights in between. This seems in contrast with the notion that the beneficial effect of sleep deprivation on mood is completely lost after one night of sleep. In the literature relapse rates in medicated patients who responded to sleep deprivation vary from 47 to 59% (review in Van den Hoofdakker, 1994). It is concluded that on average some beneficial effect of sleep deprivation on mood remains after recovery sleep. The question how long the sleep deprivation effect lasts and the issue of possible influences of the various drugs on the effects of sleep deprivation and recovery-sleep will be presented elsewhere (Gordijn et al. in prep). Significant relationships were found between variability of DV, sleep deprivation effect and recovery-sleep effect with improvement after 6 weeks of antidepressive therapy. The average DV-amplitude was not significantly correlated with treatment outcome after 6 weeks. The result that a high variability of DV, a beneficial effect of sleep deprivation and a small relapse of mood after recovery-sleep predict low depression ratings after 6 weeks of treatment is in line with our hypothesis that a high variability of DV might reflect a patients vulnerability to mood improving stimuli, such as sleep deprivation, but also to those of other antidepressive interventions. The results of the present study confirm the conclusions of the two previous studies on the predicting values of sleep deprivation and DV with respect to the response to antidepressive therapy (Wirz-Justice et al., 1979; Fähndrich, 1983). In those studies, however, the subjects were categorized as responders or non-responders to sleep deprivation and to the antidepressive treatment, while the large data set of the present study allowed a correlative analysis. In a previous study we could not find significant correlations between sleep deprivation effect on mood and therapy outcome (Bouhuys et al. subm.). This is probably due to the difference in group size between that study (25 subjects) and the present study (n=81, including those 25 subjects). We reported earlier that variability of DV was highly correlated with the effect of sleep deprivation (Gordijn et al., 1994). As was mentioned above, both variables are related to therapy outcome after 6 weeks. In the present report we studied whether these variables are independently related to depression outcome by means of a multiple regression analysis. The fact that only the sleep deprivation effect contributed significantly to therapy outcome and that variability of DV did not add significant- 44

5 ly to the explained variance suggests that both variables might be related to a common process. It is conceivable that both variability of DV and sleep-deprivation effect reflect a patients capacity to show mood changes. In summary, sleep deprivation in severely depressed inpatients might be a useful tool in antidepressive therapy. This is not only because the beneficial effects on mood might last longer than for just one day but also because a favourable TSD response predict a favourable outcome of antidepressive treatment. This study was supported by VWS grant REFERENCES Bouhuys A.L., Heeg G.P., Gordijn, M.C.M. and Beersma, D.G.M. The prediction of the 6-weeks outcome in depression from baseline activation: a study on variation in objective voice pitch, subjective energy and tension. (1998, subm). Fähndrich E (1983) Clinical and biological parameters as predictors for antidepressant drug responses in depressed patients. Pharmacopsychiat 16: Gordijn MCM, Beersma DGM, Bouhuys AL, Reinink E, and Van den Hoofdakker RH (1994) A longitudinal study of diurnal mood variation in depression; characteristics and significance. J Affect Disord 31: Gordijn, M.C.M., Beersma, D.G.M., Bouhuys A.L. and Van den Hoofdakker, R.H. Mood variability and sleep deprivation effect as predictors of therapeutic response in depression. (1998, in prep). Hamilton M (1967) Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6: Van den Hoofdakker RH (1994) Chronobiological theories of nonseasonal affective disorders and their implications for treatment. J Biol Rhythms 9: Von Zerssen D (1986) Clinical self-rating scales (CSRS) of the Munich Psychiatric Information System (PSYCHIS München). In Assessment of Depression, N Sartorius and TA Ban, eds, pp , Springer-Verlag, Berlin. Wirz-Justice A, Pühringer W, and Hole G (1979) Response to sleep deprivation as a predictor of therapeutic results with antidepressant drugs. Am J Psychiatr 136: