- Email: [email protected]
P.2.c.010 Impact of the melatonergic antidepressant agomelatine on sleep-wake rhythms of depressed patients
P.2.c Affective disorders and antidepressants – Antidepressants (clinical) the same set of simulations (same seed for all the analyses). Effect sizes for continuous outcomes (final and gain scores) were calculated as Cohen d estimates, whereas the risk difference (RD) was calculated for dichotomous outcomes (clinical response and remission) by using binomial regressions with an identity link. Following usual criteria clinical response was defined as a relative change from baseline 50% in the final HDRS-17, whereas remission was defined as a final score 7 on the HDRS-17. Results: The table reports the results of our simulations. Cohen d estimate for the gain score was a 18% lower than the corresponding estimate for final scores. The RD for the criterion of remission was a 70% lower than the corresponding estimate for clinical response. Outcomes
Placebo group (n = 60)
Antidepressant group (n = 60)
Effect sizes
Final scores; mean (95% CI) Gain scores; mean (95% CI) Clinical response; % (95% CI) Remission; % (95% CI)
16.0 (15.1 to 16.9)
11.0 (10.1 to 12.0)
−8.0 (−6.9 to −9.1)
−13.0 (−11.9 to −14.1)
14.5 (6.7 to 23.3)
64.9 (53.3 to76.7)
1.2 (0 to 5.0)
15.9 (6.7 to 25.0)
Cohen d = 1.40 (1.0 to 1.84) Cohen d = 1.15 (0.76 to 1.56) RD = 0.50 (0.35 to 0.65) RD = 0.15 (0.05 to 0.25)
Conclusions: Contrary to common beliefs combining mixed outcomes from antidepressant trials reporting final and gain scores in a meta-analysis could lead to undesirable heterogeneity among studies. The effect size estimates for gain scores are lower than the corresponding estimates when using final raw scores. Outcomes for clinical response and remission never should be combined. Study supported by University of the Basque Country (1/UPV 00212.327E-15860/2004) and Health Department-Basque Government (200411049). P.2.c.009 The incidence of antidepressant-associated mania and hypomania in major depression
S317
data, age of illness onset, medical and psychiatric comorbidity, duration of illness, and psychiatric family history in first degree relatives was obtained. Mania and hypomania were diagnosed according to DSM-IV criteria. Continuous variables were analyzed using independent t-test, and categorical variables were analyzed with a chi-square or Fisher’s exact test. Results: Of 232 major depressive disorder patients, sixty six patients were treated with tricyclic antidepressants (TCAs) including amitriptyline (n = 42), dothiepin (n = 17) and nortriptyline (n = 7). Patients prescribed selective serotonin reuptake inhibitors (SSRIs) were 202; paroxetine (n = 141), fluoxetine (n = 44), citalopram (n = 9), and sertraline (n = 8). Mirtazapine was administrated to 110 patients, trazodone to 83 patients, venlafaxine to 39 patients, and other antidepressants to 9 patients. TCAs and trazodone were used in low dose adjunctively for sleep induction. Switches to hypomania or mania occurred in 12 patients (5.2%); 4.3% (n = 10) experienced hypomanic episodes, and 0.9% (n = 2) experienced manic episodes. Hypomanic and manic episodes are associated with paroxetine (n = 5, 3.5%, mean dose = 38.0 mg/day), mirtazapine (n = 3, 2.7%, mean dose = 45 mg/day), venlafaxine (n = 2, 5.1%, mean dose = 150 mg/day), fluoxetine (n = 2, 4.5%, mean dose = 30 mg/day), sertraline (n = 1, 1.3%, mean dose = 150 mg/day), trazodone (n = 1, 1.2%, mean dose = 50 mg/day), and amitriptyline (n = 1, 2.4%, mean dose = 100 mg/day). These results include three patients treated with combination regimen (paroxetine + trazodone, paroxetine + amitriptyline, fluoxetine + venlafaxine). Significant difference was found in mean age of illness onset between switchers (38.5±11.4) and nonswitchers (48.4±17.0) (p < 0.05). Proportion of females, medical and psychiatric comorbidity, duration of illness, and psychiatric family history in first degree relatives were not significantly different. Conclusion: The frequency of manic/hypomanic switching associated with antidepressant treatment was not different from pooled data show that mood switches occur with antidepressants in 0.4%-11% of patients. Moreover, this study provides the evidence that earlier age at illness onset was predictive of switches. References
W.M. Bahk1 ° , Y.S. Woo1 , J.H. Chae1 , J.H. Choi2 , T.Y. Jun1 , K.S. Kim1 , W. Kim3 . 1 The Catholic University of Korea, Psychiatry, Seoul, Republic of Korea; 2 National Medical Center, Psychiatry, Seoul, Republic of Korea; 3 Seoul Paik Hospital, Inje University, Psychiatry, Seoul, Republic of Korea Objectives: Antidepressants have been reported to precipitate or induce mania or hypomania in patients with unipolar and bipolar disorder. The rate of antidepressant associated manic/ hypomanic switch in unipolar depression ranges from 0.4% to 11%, which is lower than bipolar depression ranges from 2.2% to 70%. However, the incidence of antidepressant associated manic/ hypomanic switch is not negligible in clinical practice. Possible risk factors for antidepressant-associated mania are female gender, younger age, high doses of antidepressant, and previous family psychiatric history. The aim of the present study was to find the incidence of mania and hypomania in 232 patients presenting for treatment of a DSM-IV major depressive disorder in a university hospital, during a follow-up of 12 to 24 months. Method: Subjects in this study were patients who were outpatients followed in the St. Mary’s hospital, Seoul, Korea between January 2002 and December 2004 who met DSM-IV criteria for major depressive disorder. We conducted retrospective medical record review to examine the dosage and name of antidepressant prescribed. Detailed clinical information including demographic
[1] Benazzi F., 1997, Antidepressant-associated hypomania in outpatient depression: A 203-case study in private practice, J Affect Disord, 46, 73−77. [2] Ramasubbu R., 2001, Dose-response relationship of selective serotonin reuptake inhibitors treatment-emergent hypomania in depressive disorders, Acta Psychiatr Scand, 104, 236–239.
P.2.c.010 Impact of the melatonergic antidepressant agomelatine on sleep–wake rhythms of depressed patients C. Guilleminault1 ° , M.A. Quera-Salva2 . 1 Stanford Sleep Disorders Center, Psychiatry and Behavioral Sciences, Stanford, USA; 2 Raymond Poincare Hospital, Sleep Unit, Garches, France Objective: Sleep disturbances are among the most important and disabling symptoms of Major Depressive Disorder (MDD). About 70% of outpatients with major depression report difficulties initiating and maintaining sleep as well as early morning awakening. Agomelatine is a new antidepressant which possesses a unique pharmacological profile, being an agonist of melatonergic MT1 and MT2 receptors and an antagonist of 5-HT2C receptors. Agomelatine has been shown to be effective in MDD in several trials [1−3]. The aim of the present study is to demonstrate
S318
P.2.c Affective disorders and antidepressants – Antidepressants (clinical)
the beneficial effects of agomelatine in sleep disturbances of depressed patients. Methods: Two specific studies were conducted with patients suffering from MDD. In the first study, patients were given agomelatine 25 mg in open conditions in the evening for 42 days and polysomnography was performed at baseline, D7, D14 and D42. In the second study, which was a comparative doubleblind randomized trial, patients were given agomelatine 25−50 mg or venlafaxine 75–150 mg for 6 weeks and subjective sleep evaluations (Leeds sleep evaluation questionnaire [LSEQ] and visual analogue scales [VAS] to study the impact on the daytime condition) were carried out every week. Finally, a meta-analysis of the sleep items of the Hamilton Depression Scale (HAMD) of the three short-term placebo-controlled pivotal efficacy studies carried out with agomelatine 25−50 mg was undertaken. Results: Fifteen ambulatory patients (20 to 56 years old, male or female) with a new major depressive episode were included in the open polysomnography study. Agomelatine showed an increase in sleep efficiency and in slow-wave sleep (SWS) time. No effect was seen in different REM sleep indexes but there was normalization of SWS and REM sleep distribution over each sleep cycle with associated normalization of delta power. In the double-blind, 6-week study, ambulatory male or female (18 to 65 years old) patients were treated with agomelatine (n = 165) or venlafaxine (n = 167). The two treatments showed a similar antidepressant efficacy but agomelatine-treated patients had a significantly better sleep improvement than those treated with venlafaxine. This effects could be observed as early as the first week of treatment (P = 0.007 in getting off to sleep and P = 0.015 for quality of sleep) and lasted until the end of the 6 weeks of treatment. Concomitantly, a significant (P 0.001 at week 1) early improvement in the daytime condition (daytime sleepiness and feeling good VAS items) was demonstrated for agomelatine compared with venlafaxine. In the meta-analysis of the HAMD sleep subscale, agomelatine was more effective than placebo on all three phases of sleep, early insomnia (P < 0.001), middle insomnia (P = 0.015) and early awakening (P = 0.006). Conclusion: Agomelatine, a novel approach to the treatment of depression, combines antidepressant efficacy with the benefit of sleep improvement in depressed patients. This provides an important clinical advantage among the available antidepressant treatments. References [1] Loo H, Hale A, D’haenen H, 2002, Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: A placebo-controlled dose range study, Int Clin Psychopharmacol, 17, 239–247. [2] Kennedy S, Emsley R, 2006, Placebo-controlled trial of agomelatine in the treatment of major depressive disorder, Eur Neuropsychopharmacol, 16, 93–100. [3] Olie J-P, Emsley R, 2005, Confirmed clinical efficacy of agomelatine (25−50 mg) in major depression: two randomized double-blind, placebo-controlled studies, Eur Neuropsychopharmacol, 15, suppl 3, S416.
P.2.c.011 Effects of a phytopharmacal triple combination of St. John’s wort, valerian and passion flower on sleep EEG, cognitive performance and mood: a double-blind randomised cross-over study in healthy volunteers U.M. Hemmeter1 ° , A. Thum1 , M. Giesler1 , A. Haag1 , A. Wartenberg-Demand2 , G.P. McGregor2 , B. Kundermann1 ,
J.C. Krieg1 . 1 University of Marburg, Clinic of Psychiatry and Psychotherapy, Marburg, Germany; 2 Pascoe pharmaceutical Preparations GmbH, clinical research, Giessen, Germany Almost all drugs for treating insomnia in depression improve sleep, but worsen cognitive performance. Phytotherapeutics, such as St. John’s, valerian and passion flower, improve depression, anxiety (St. John’s wort, passion flower) and sleep (valerian) without affecting cognitive performance. Neurapas balance is a triple combination of these three extracts, which is widely used for treating minor depression and anxiety states in Germany which are frequently accompanied by sleep disturbance. Concerning the intake of phytotherapeutics ist is still matter of debate, whether the subjectively experienced effects by the patients represent a mere psychological or placebo phenomenon or whether these effects are mediated by central nervous actions of these compounds. In order to evaluate whether Neurapas balance exerts central nervous effects, in this study, we tested the effect of Neurapas balance on sleep-EEG, mood and cognitive performance in order in volunteers. 20 healthy subjects were examined twice in a double-blind, randomized cross-over design and received either placebo or Neurapas balance (3×2 tablets over 3 days consisting of 60 mg St. John’s wort, 28 mg valerian, 35 mg passion flower ( = 1 tabl.). Dependent variables were sleep-EEG parameters, subjective mood (BSKE), vegetative symptoms (MSKL), subjective sleep estimation and tests of cognitive psychomotor performance including vigilance, functions of simple and divided attention and declarative memory. Statistical comparisons between placebo and NP have been performed by Wilcoxon tests. The results revealed that Neurapas balance reduced wakefulness in the first part of sleep (3.8±2.7 vs. 9.3±12.9 min., p < 0.02), REM-latency (72±26.0 vs. 97.7±32.6, p < 0.01) and NonREM-sleep in the first sleep cycle, which was compensated by an increase of NonREMsleep in the second cycle (82.4±15.9 vs. 70.4±16.7, p < 0.02). Positive trend effects of Neurapas balance were found for the items, mental agitation and melancholy (BSKE), hand-trembling and hand-moisture (MSKL). No differences between NB and placebo were detected in the tests of cognitive performance (Wilcoxon-tests n.s.). These findings show that Neurapas balance exerts central nervous effects as reflected by changes in sleep EEG, predominantly sleep architecture. Furthermore, sleep continuity, and some aspects of subjective mood and subjective sleep evaluation were improved. These effects are remarkable, because they could be observed even in healthy subjects without major emotional and/or sleep disturbance. Furthermore, no negative effects of Neurapas balance on cognitive performance have been observed. The results of this study in volunteers indicate that Neurapas balance has distinct neurophysiological effects and can improve subjective feelings even in healthy subjects. The observed effects on sleep EEG are in part comparable to effects of St. John’s wort on polysomnography in depressed patients. It is possible that the observed behavioural effects may mediated by the effects on sleep EEG detected in this study. However, the relationship of these neurobiological changes induced by Neurapas balance to the observed behavioural effects of Neurapas balance and further phytotherapeuticcs has to be further clarified. References [1] Holsboer-Trachsler E, Brand S, Hatzinger M, Hemmeter U, 2001, Effects of hypericum extract on sleep-EEG and Dex-CRH-test in patients with depression, Biol Psychiatry, 49, 9S. [2] Wheatley D, 2005, Medical plants for insomnia: a review of their pharmacology, efficacy and tolerability, J of Psychopharmacology, 19, 4, 414–421.
Placebo group (n = 60)
Antidepressant group (n = 60)
Effect sizes
Final scores; mean (95% CI) Gain scores; mean (95% CI) Clinical response; % (95% CI) Remission; % (95% CI)
16.0 (15.1 to 16.9)
11.0 (10.1 to 12.0)
−8.0 (−6.9 to −9.1)
−13.0 (−11.9 to −14.1)
14.5 (6.7 to 23.3)
64.9 (53.3 to76.7)
1.2 (0 to 5.0)
15.9 (6.7 to 25.0)
Cohen d = 1.40 (1.0 to 1.84) Cohen d = 1.15 (0.76 to 1.56) RD = 0.50 (0.35 to 0.65) RD = 0.15 (0.05 to 0.25)
Conclusions: Contrary to common beliefs combining mixed outcomes from antidepressant trials reporting final and gain scores in a meta-analysis could lead to undesirable heterogeneity among studies. The effect size estimates for gain scores are lower than the corresponding estimates when using final raw scores. Outcomes for clinical response and remission never should be combined. Study supported by University of the Basque Country (1/UPV 00212.327E-15860/2004) and Health Department-Basque Government (200411049). P.2.c.009 The incidence of antidepressant-associated mania and hypomania in major depression
S317
data, age of illness onset, medical and psychiatric comorbidity, duration of illness, and psychiatric family history in first degree relatives was obtained. Mania and hypomania were diagnosed according to DSM-IV criteria. Continuous variables were analyzed using independent t-test, and categorical variables were analyzed with a chi-square or Fisher’s exact test. Results: Of 232 major depressive disorder patients, sixty six patients were treated with tricyclic antidepressants (TCAs) including amitriptyline (n = 42), dothiepin (n = 17) and nortriptyline (n = 7). Patients prescribed selective serotonin reuptake inhibitors (SSRIs) were 202; paroxetine (n = 141), fluoxetine (n = 44), citalopram (n = 9), and sertraline (n = 8). Mirtazapine was administrated to 110 patients, trazodone to 83 patients, venlafaxine to 39 patients, and other antidepressants to 9 patients. TCAs and trazodone were used in low dose adjunctively for sleep induction. Switches to hypomania or mania occurred in 12 patients (5.2%); 4.3% (n = 10) experienced hypomanic episodes, and 0.9% (n = 2) experienced manic episodes. Hypomanic and manic episodes are associated with paroxetine (n = 5, 3.5%, mean dose = 38.0 mg/day), mirtazapine (n = 3, 2.7%, mean dose = 45 mg/day), venlafaxine (n = 2, 5.1%, mean dose = 150 mg/day), fluoxetine (n = 2, 4.5%, mean dose = 30 mg/day), sertraline (n = 1, 1.3%, mean dose = 150 mg/day), trazodone (n = 1, 1.2%, mean dose = 50 mg/day), and amitriptyline (n = 1, 2.4%, mean dose = 100 mg/day). These results include three patients treated with combination regimen (paroxetine + trazodone, paroxetine + amitriptyline, fluoxetine + venlafaxine). Significant difference was found in mean age of illness onset between switchers (38.5±11.4) and nonswitchers (48.4±17.0) (p < 0.05). Proportion of females, medical and psychiatric comorbidity, duration of illness, and psychiatric family history in first degree relatives were not significantly different. Conclusion: The frequency of manic/hypomanic switching associated with antidepressant treatment was not different from pooled data show that mood switches occur with antidepressants in 0.4%-11% of patients. Moreover, this study provides the evidence that earlier age at illness onset was predictive of switches. References
W.M. Bahk1 ° , Y.S. Woo1 , J.H. Chae1 , J.H. Choi2 , T.Y. Jun1 , K.S. Kim1 , W. Kim3 . 1 The Catholic University of Korea, Psychiatry, Seoul, Republic of Korea; 2 National Medical Center, Psychiatry, Seoul, Republic of Korea; 3 Seoul Paik Hospital, Inje University, Psychiatry, Seoul, Republic of Korea Objectives: Antidepressants have been reported to precipitate or induce mania or hypomania in patients with unipolar and bipolar disorder. The rate of antidepressant associated manic/ hypomanic switch in unipolar depression ranges from 0.4% to 11%, which is lower than bipolar depression ranges from 2.2% to 70%. However, the incidence of antidepressant associated manic/ hypomanic switch is not negligible in clinical practice. Possible risk factors for antidepressant-associated mania are female gender, younger age, high doses of antidepressant, and previous family psychiatric history. The aim of the present study was to find the incidence of mania and hypomania in 232 patients presenting for treatment of a DSM-IV major depressive disorder in a university hospital, during a follow-up of 12 to 24 months. Method: Subjects in this study were patients who were outpatients followed in the St. Mary’s hospital, Seoul, Korea between January 2002 and December 2004 who met DSM-IV criteria for major depressive disorder. We conducted retrospective medical record review to examine the dosage and name of antidepressant prescribed. Detailed clinical information including demographic
[1] Benazzi F., 1997, Antidepressant-associated hypomania in outpatient depression: A 203-case study in private practice, J Affect Disord, 46, 73−77. [2] Ramasubbu R., 2001, Dose-response relationship of selective serotonin reuptake inhibitors treatment-emergent hypomania in depressive disorders, Acta Psychiatr Scand, 104, 236–239.
P.2.c.010 Impact of the melatonergic antidepressant agomelatine on sleep–wake rhythms of depressed patients C. Guilleminault1 ° , M.A. Quera-Salva2 . 1 Stanford Sleep Disorders Center, Psychiatry and Behavioral Sciences, Stanford, USA; 2 Raymond Poincare Hospital, Sleep Unit, Garches, France Objective: Sleep disturbances are among the most important and disabling symptoms of Major Depressive Disorder (MDD). About 70% of outpatients with major depression report difficulties initiating and maintaining sleep as well as early morning awakening. Agomelatine is a new antidepressant which possesses a unique pharmacological profile, being an agonist of melatonergic MT1 and MT2 receptors and an antagonist of 5-HT2C receptors. Agomelatine has been shown to be effective in MDD in several trials [1−3]. The aim of the present study is to demonstrate
S318
P.2.c Affective disorders and antidepressants – Antidepressants (clinical)
the beneficial effects of agomelatine in sleep disturbances of depressed patients. Methods: Two specific studies were conducted with patients suffering from MDD. In the first study, patients were given agomelatine 25 mg in open conditions in the evening for 42 days and polysomnography was performed at baseline, D7, D14 and D42. In the second study, which was a comparative doubleblind randomized trial, patients were given agomelatine 25−50 mg or venlafaxine 75–150 mg for 6 weeks and subjective sleep evaluations (Leeds sleep evaluation questionnaire [LSEQ] and visual analogue scales [VAS] to study the impact on the daytime condition) were carried out every week. Finally, a meta-analysis of the sleep items of the Hamilton Depression Scale (HAMD) of the three short-term placebo-controlled pivotal efficacy studies carried out with agomelatine 25−50 mg was undertaken. Results: Fifteen ambulatory patients (20 to 56 years old, male or female) with a new major depressive episode were included in the open polysomnography study. Agomelatine showed an increase in sleep efficiency and in slow-wave sleep (SWS) time. No effect was seen in different REM sleep indexes but there was normalization of SWS and REM sleep distribution over each sleep cycle with associated normalization of delta power. In the double-blind, 6-week study, ambulatory male or female (18 to 65 years old) patients were treated with agomelatine (n = 165) or venlafaxine (n = 167). The two treatments showed a similar antidepressant efficacy but agomelatine-treated patients had a significantly better sleep improvement than those treated with venlafaxine. This effects could be observed as early as the first week of treatment (P = 0.007 in getting off to sleep and P = 0.015 for quality of sleep) and lasted until the end of the 6 weeks of treatment. Concomitantly, a significant (P 0.001 at week 1) early improvement in the daytime condition (daytime sleepiness and feeling good VAS items) was demonstrated for agomelatine compared with venlafaxine. In the meta-analysis of the HAMD sleep subscale, agomelatine was more effective than placebo on all three phases of sleep, early insomnia (P < 0.001), middle insomnia (P = 0.015) and early awakening (P = 0.006). Conclusion: Agomelatine, a novel approach to the treatment of depression, combines antidepressant efficacy with the benefit of sleep improvement in depressed patients. This provides an important clinical advantage among the available antidepressant treatments. References [1] Loo H, Hale A, D’haenen H, 2002, Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: A placebo-controlled dose range study, Int Clin Psychopharmacol, 17, 239–247. [2] Kennedy S, Emsley R, 2006, Placebo-controlled trial of agomelatine in the treatment of major depressive disorder, Eur Neuropsychopharmacol, 16, 93–100. [3] Olie J-P, Emsley R, 2005, Confirmed clinical efficacy of agomelatine (25−50 mg) in major depression: two randomized double-blind, placebo-controlled studies, Eur Neuropsychopharmacol, 15, suppl 3, S416.
P.2.c.011 Effects of a phytopharmacal triple combination of St. John’s wort, valerian and passion flower on sleep EEG, cognitive performance and mood: a double-blind randomised cross-over study in healthy volunteers U.M. Hemmeter1 ° , A. Thum1 , M. Giesler1 , A. Haag1 , A. Wartenberg-Demand2 , G.P. McGregor2 , B. Kundermann1 ,
J.C. Krieg1 . 1 University of Marburg, Clinic of Psychiatry and Psychotherapy, Marburg, Germany; 2 Pascoe pharmaceutical Preparations GmbH, clinical research, Giessen, Germany Almost all drugs for treating insomnia in depression improve sleep, but worsen cognitive performance. Phytotherapeutics, such as St. John’s, valerian and passion flower, improve depression, anxiety (St. John’s wort, passion flower) and sleep (valerian) without affecting cognitive performance. Neurapas balance is a triple combination of these three extracts, which is widely used for treating minor depression and anxiety states in Germany which are frequently accompanied by sleep disturbance. Concerning the intake of phytotherapeutics ist is still matter of debate, whether the subjectively experienced effects by the patients represent a mere psychological or placebo phenomenon or whether these effects are mediated by central nervous actions of these compounds. In order to evaluate whether Neurapas balance exerts central nervous effects, in this study, we tested the effect of Neurapas balance on sleep-EEG, mood and cognitive performance in order in volunteers. 20 healthy subjects were examined twice in a double-blind, randomized cross-over design and received either placebo or Neurapas balance (3×2 tablets over 3 days consisting of 60 mg St. John’s wort, 28 mg valerian, 35 mg passion flower ( = 1 tabl.). Dependent variables were sleep-EEG parameters, subjective mood (BSKE), vegetative symptoms (MSKL), subjective sleep estimation and tests of cognitive psychomotor performance including vigilance, functions of simple and divided attention and declarative memory. Statistical comparisons between placebo and NP have been performed by Wilcoxon tests. The results revealed that Neurapas balance reduced wakefulness in the first part of sleep (3.8±2.7 vs. 9.3±12.9 min., p < 0.02), REM-latency (72±26.0 vs. 97.7±32.6, p < 0.01) and NonREM-sleep in the first sleep cycle, which was compensated by an increase of NonREMsleep in the second cycle (82.4±15.9 vs. 70.4±16.7, p < 0.02). Positive trend effects of Neurapas balance were found for the items, mental agitation and melancholy (BSKE), hand-trembling and hand-moisture (MSKL). No differences between NB and placebo were detected in the tests of cognitive performance (Wilcoxon-tests n.s.). These findings show that Neurapas balance exerts central nervous effects as reflected by changes in sleep EEG, predominantly sleep architecture. Furthermore, sleep continuity, and some aspects of subjective mood and subjective sleep evaluation were improved. These effects are remarkable, because they could be observed even in healthy subjects without major emotional and/or sleep disturbance. Furthermore, no negative effects of Neurapas balance on cognitive performance have been observed. The results of this study in volunteers indicate that Neurapas balance has distinct neurophysiological effects and can improve subjective feelings even in healthy subjects. The observed effects on sleep EEG are in part comparable to effects of St. John’s wort on polysomnography in depressed patients. It is possible that the observed behavioural effects may mediated by the effects on sleep EEG detected in this study. However, the relationship of these neurobiological changes induced by Neurapas balance to the observed behavioural effects of Neurapas balance and further phytotherapeuticcs has to be further clarified. References [1] Holsboer-Trachsler E, Brand S, Hatzinger M, Hemmeter U, 2001, Effects of hypericum extract on sleep-EEG and Dex-CRH-test in patients with depression, Biol Psychiatry, 49, 9S. [2] Wheatley D, 2005, Medical plants for insomnia: a review of their pharmacology, efficacy and tolerability, J of Psychopharmacology, 19, 4, 414–421.