- Email: [email protected]
P.2.c.024 024 Association study between BDNF genetic polymorphism and treatment responses of SSRI in major depressive disorder
P.2.c Affective disorders and antidepressants - Antidepressants (clinical)
being diagnosed with MDD according to DSM-IV-TR criteria, not having co-morbid psychopathology or any chronic medical disorder, using SSRIS at least for 6 weeks before the study, having a CGI-S severity score of 4, and providing informed consent. A control group was formed from patients who were diagnosed with MDD but were free of drugs for the last month. Both the patients and controls should have to have a stable, sexual relationship for inclusion. The groups were matched in terms of gender, smoking! alcohol use, presence of marital problems, sexual dysfunction prior to disorder and! or treatment, severity of MDD, and using contraception. The Arizona Sexual Experience Scale (ASEX) was given to both groups and those who score above the cut-off score were deemed to have sexual dysfunction. Those with sexual dysfunction were then compared with those without. The SPSS 15.0 for Windows (Chicago, IL., USA) program was used in statistical analysis. P was set at 0.05. Results: The study group consisted of 19 patients (13 female, 68.4 %) while the control group was formed of 14 patients (12 female, 85.7 %). The mean age of the study and control groups were 32.2 (SD 12.0) and 33.7 (SD 10.5) years, respectively. The mean ASEX scores for the study group were 18.9 (SD 4.6) for females and 17.3 (SD 3.5) for males. The corresponding scores in the control group were 17 (SD 6.6) for females and 15.4 (4.1) for males. The groups did not differ significantly for age, education years and ASEX scores, either for males or females (Mann Whitney U test). 14 patients on SSRIS (73.7 %) and 12 controls (% 85.7) displayed sexual dysfunction and there were no significant differences in between groups (Chi Square test). Being female was significantly associated with sexual dysfunction whether the patient was on SSRI or not (Chi square: 5.2, df: 1, p:0.04). Patients with sexual dysfunction differed in arousal, according to ASEX (Z=-2.016, p=0.05, Mann-Whitney U test). Conclusions: The primary finding of our study is the high prevalence of sexual dysfunction both in medicated and in unmedicated Turkish patients with MDD. This may be due to the effects of depression itself. It seems that the arousal stage is especially affected. The prevalence of sexual dysfunction in Turkish patients with MDD, both on and off SSRIs should be clarified with further, longitudinal studies conducted on same sex samples. References [1] Segraves, R. T. 1989 Effects of psychotropic drugs on human erection and ejaculation. Arch Gen Psychiatry, 46, 275-284. [2] Landen, M., Hogberg, P., Thase, M. E. 2005 Incidence of sexual side effects in refractory depression during treatment with citaloprarn or paroxetine. J C1in Psychiatry, 66, 100-106. [3] Montejo-Gonzalez, A. L., Llorca, G., Izquierdo, J. A., Ledesma, A., Bousono, M., Ca1cedo, A., Carrasco, J. L., Ciudad, J., Daniel, E., De 1a Gandara, J., Derecho, J., Franco, M., Gomez, M. J., Macias, J. A., Martin, T., Perez, Sanchez, J. M., Sanchez, S., & Vicens, E. 1997 SSRI-induced sexual dysfunction: F1uoxetine, paroxetine, sertra1ine, and fluvoxamine in a prospective, multicenter, and descriptive study of 344 patients. J Sex Marital Ther, 23, 176-194
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1P.2.c.0241 Association study between BDNF genetic polymorphism and treatment responses of SSRI in major depressive disorder Y. Lee 1 ., Y. Jung1, 1. Park1 , S. Kim 1 , 1. Kim 1, C. Kang 1 , B. Lee 1 , D. Lee2 . 1Pusan National University Hospital, Department of Psychiatry, Busan, South-Korea; 2 Good Gangan General Hospital, Department ofPsychiatry, Busan, South-Korea Background: brain-derived neurotrophic factor (BDNF) is recognized as playing an important role in the survival, differentiation, and outgrowth of select peripheral and central neurons during development and in adulthood. Recent studies suggest that BDNF may playa critical role in both mechanism of antidepressant action and the pathophysiology of major depressive disorder (MDD). The aim of this study is to evaluate whether the BDNF-gene Val66Met polymorphism is associated with susceptibility ofMDD, and antidepressant response in a Korean population. Methods: One hundred thirty-seven patients with MDD and 91 control subjects were recruited and analyzed for this study. Psychiatric diagnoses were carried out using the Korean version of the Structured Clinical Interview for DSM-IV Axis-I disorder (SCIDIV). The severity of depression was measured using the 17-item Hamilton Rating Scale for Depression (HAM-D-17) for MDD patients before and after a 6-week treatment with the antidepressant, Selective Serotonin Reuptake Inhibitor. A minimum baseline HAM-D-17 score of 15 was required for study inclusion. Treatment outcome was measured as response (~50% improvement on HAM-D-17) and remission (final HAM-D-17 ~7). Ninetyone healthy controls were matched by age, sex and education. Control subjects were non-smokers, were not on medication and had no history of major psychiatric disorders, dementia, mental retardation, cancer or tumor and no such disorders in their firstdegree relatives. Five milliliters of blood were withdrawn from each subject by venipuncture into an ethylene diarnine tetraactic acid(EDTA) vacuum tube for DNA analyses. The genotypes of BDNF Val66Met polymorphism in all subject were determined using polymerase chain reaction(PCR). All the assays were performed blind to the subject's status. we examined the association of the BDNF-gene Val66Met polymorphism and therapeutic response in 137 MDD patients who received a 6-week Selective Serotonin Reuptake Inhibitor(SSRI) treatment. Results: There were no significant differences in age and gender distribution between the MDD and control groups. Both samples were found to be Hardy-Weinberg equilibrium (MDD X,2=0.125, df= 1, p=0.723; Control )(2=0.093, df= 1, p=0.759). The genotype or allele frequency of the BDNF polymorphism did not differ significantly between the MDD and control subjects()(2=0.635, df=2, p=0.728). No significant differences were noted in the three-genotype MDD groups (ValNal, VallMet, Met/Met) between responders and non-responders. However, heterozygous patients (VallMet) in comparison to homozygous analogs (ValNal or Met/Met) in BDNF polymorphism tended to have more improved 6-week antidepressant response(p = 0.053). In addition, higher total HAM-D-score percentage change after 6 weeks of antidepressant medication was demonstrated for the heterozygote patients in comparison to homozygous analogs(p = 0.006). Conclusion: This finding suggests the BDNF polymorphism is associated with improved therapeutic SSRI response for patients bearing the BDNF VallMet heterozygote in comparison to the homozygous analogs(ValNal or Met/Met). Nevertheless, the pos-
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P.2.c Affective disorders and antidepressants - Antidepressants (clinical)
sibility of false positive findings suggests that further studies are necessary to replicate the findings. References
[1] Choi MJ, Kang RH, Lim Sw, Dh KS, Lee MS. 2006 Brain-derived neurotrophic factor gene polymorphism (Va166Met) and citalopram response in major depressive disorder. Brain Res. 1118:176-182. [2] Tsai SJ, Cheng CY, Yu Yw, Chen TJ, Hong CI 2003 Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet. 123:19-22. [3] Hashimoto K, Shimizu E, Iyo M. 2004 Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev. 45:104-114.
1P.2.C.0251 Early pain response associated with better outcome in emotional symptoms in depressive patients treated with duloxetine E. Schneider1 ., U. Heger12 , M. Linden3 , D. Quail4 , T. Wagner1, H.P. Hundemer1 . 1Lilly Deutschland GmbH, Medical Department, Bad Homburg, Germany; 2 University of Leipzig, Department ofPsychiatry, Leipzig, Germany; 3 Charite University Medicine, Research Group Psychosomatic Rehabilitation, Berlin, Germany; 4Eli Lilly and Co Ltd, European Medical Information Sciences, Windlesham, United Kingdom Purpose: Primary research objective of this observational study was to investigate the association of the change of painful physical symptoms (PPS) during the first 4 weeks, with long-term treatment outcomes of emotional symptoms of depression in patients treated with du10xetine (DLX) in clinical practice. Design and Methods: Multicenter, prospective, 6-month observational study in adult outpatients with a depressive episode (according to ICD-lO) at 693 centers in Germany, starting treatment with DLX. Depression severity was assessed by the clinicianrated 'Inventory for Depressive Symptomatology' (IDS-C) scale, and 'Kurz-Skala Stimmung/Aktivierung' (KUSTA), comprising the items mood, activity, tension/relaxation and sleep; each rated on a visual analog scale (VAS) by the patients. Somatic symptoms and PPS were assessed using the self-rated 'Somatic Symptom Inventory' (SSI) and VAS for pain items. To investigate the association of the change of PPS with outcomes of emotional symptoms, the mean of the KUSTA items and achievement of a 50% reduction in the total IDS-C score at the final visit were analyzed using linear and logistic regression models, respectively. Results: Of the 4,517 patients enrolled (mean age 52.2 years, 71.8% female), 3,320 patients (73.5%) completed the study. The majority ofthe depressed patient population (80.0%) had moderate to severe overall pain (VAS >30mm) at baseline (BL). During DLX treatment, the IDS-C total score (mean (SD)) decreased from BL to 6 months from 39.2 (12.4) to 16.1 (11.9) and the mean KUSTA score increased from 25.2 (16.8) to 58.9 (25.9), both scales indicating improvement of emotional symptoms. The SSI total score (mean (SD)) decreased from 2.47 (0.69) to 1.72 (0.65) and the VAS overall pain from 55.0mm (26.6mm) to 30.5 mm (25.4 mm), indicating improvement of somatic symptoms and PPS. A clinically relevant pain reduction (VAS) of ~30% and ~50% was reported by 61.9% and 48.1% of the patients, respectively. The linear regression analysis of the mean KUSTA score showed that a 50% reduction in overall pain VAS during the first 4 weeks, of the variables tested, had the strongest association with the mean KUSTA score at 6 months. This effect was estimated
to be 13.32 [95%CI 11.24-15.39] points on the KUSTA, which indicates that patients with a ~50% pain reduction after 4 weeks, on average, had a 13.32 point higher mean KUSTA score after 6 months, compared to patients without a ~50% reduction in overall pain. Also, a 50% reduction in overall pain VAS during the first 2 weeks was identified as having a statistically significant effect on the mean KUSTA score at 6 months. For patients with a ~50% reduction in their overall pain VAS during the first 4 weeks, the chance of achieving a 50% reduction in the IDS-C total score after 6 months was 3.00 times higher (95%CI 2.41-3.75) than for those who did not. No unexpected adverse events were found in this naturalistic study. Conclusions: This observational study found a strong association between an early pain response and an improved long-term outcome in emotional symptoms of depression in patients treated with DLX in clinical practice. Research was funded by Lilly Deutschland GmbH, Bad Homburg, Germany.
1P.2.c.0261 Superior antidepressant efficacy of agomelatine vs f1uoxetine in severe major depressive disorder patients: a randomised, double-blind study A. Hale 1 ., R. Corral2 , O. Mencacci3 , J. Saiz Ruiz'l, C. Albarran 1 Sf Martin Hospital, Eastern Sever05 , V. Gentil6 . and Costal Headquarters, Kent, United Kingdom; 2 Centro de Neuropsiquiatria, Neuropsiquiatria, Buenos Aires, Argentina; 3Azienda Ospedaliera Fatebenefratelli e Oftalmico, Salute Mentale, Milano, Italy; 4 Hospital Ramon Y Cajal, Psiquiatria, Madrid, Spain; 5Institut de recherches internationales Servier, Neuro-psychiatry, Courbevoie, France; 6 Instituto de Psiquiatria do Hospital das Clinicas, Psiquiatria, Silo Paulo, Brazil
s
Aim: Agomelatine is a new antidepressant offering a uuique approach to the management of depressive disorders, through its action as a MTlIMT2 receptors' agonist and a 5-HT2C receptor' antagonist. Its efficacy in Major Depressive Disorder (MDD) has been evidenced in several clinical trials, including one in severely depressed patients [1--4]. The aim ofthis study was to demonstrate agomelatine's superiority over fluoxetine, in severely depressed outpatients. Methods: A multinational, multicentric, randomised, doubleblind, parallel groups comparative study of agomelatine 25mg/50mg versus fluoxetine 20mg/40mg for 8-weeks of treatment, with the possibility for blind dose-adjustments respectively at W2 or at W4, in out-patients with a current severe episode of Major Depressive Disorder according to DSM-IV-TR criteria. Severity was defined by HAM-D17 total score equal or greater than 25, combined with a CGI severity of illness score equal or greater than 4. The primary efficacy criteria was the HAM-D17 total score (comparison of the change from baseline to last post-baseline value over the 8-week period between agomelatine and fluoxetine). A stepwise strategy was set-up concerning the main analysis. First the non-inferiority of agomelatine relative to fluoxetine, then in case of a significant non-inferiority test, the superiority of agomelatine versus fluoxetine was studied. These two analyses were carried out in the FAS on the change from baseline to last post-baseline value over the 8-week period, using a two-way
being diagnosed with MDD according to DSM-IV-TR criteria, not having co-morbid psychopathology or any chronic medical disorder, using SSRIS at least for 6 weeks before the study, having a CGI-S severity score of 4, and providing informed consent. A control group was formed from patients who were diagnosed with MDD but were free of drugs for the last month. Both the patients and controls should have to have a stable, sexual relationship for inclusion. The groups were matched in terms of gender, smoking! alcohol use, presence of marital problems, sexual dysfunction prior to disorder and! or treatment, severity of MDD, and using contraception. The Arizona Sexual Experience Scale (ASEX) was given to both groups and those who score above the cut-off score were deemed to have sexual dysfunction. Those with sexual dysfunction were then compared with those without. The SPSS 15.0 for Windows (Chicago, IL., USA) program was used in statistical analysis. P was set at 0.05. Results: The study group consisted of 19 patients (13 female, 68.4 %) while the control group was formed of 14 patients (12 female, 85.7 %). The mean age of the study and control groups were 32.2 (SD 12.0) and 33.7 (SD 10.5) years, respectively. The mean ASEX scores for the study group were 18.9 (SD 4.6) for females and 17.3 (SD 3.5) for males. The corresponding scores in the control group were 17 (SD 6.6) for females and 15.4 (4.1) for males. The groups did not differ significantly for age, education years and ASEX scores, either for males or females (Mann Whitney U test). 14 patients on SSRIS (73.7 %) and 12 controls (% 85.7) displayed sexual dysfunction and there were no significant differences in between groups (Chi Square test). Being female was significantly associated with sexual dysfunction whether the patient was on SSRI or not (Chi square: 5.2, df: 1, p:0.04). Patients with sexual dysfunction differed in arousal, according to ASEX (Z=-2.016, p=0.05, Mann-Whitney U test). Conclusions: The primary finding of our study is the high prevalence of sexual dysfunction both in medicated and in unmedicated Turkish patients with MDD. This may be due to the effects of depression itself. It seems that the arousal stage is especially affected. The prevalence of sexual dysfunction in Turkish patients with MDD, both on and off SSRIs should be clarified with further, longitudinal studies conducted on same sex samples. References [1] Segraves, R. T. 1989 Effects of psychotropic drugs on human erection and ejaculation. Arch Gen Psychiatry, 46, 275-284. [2] Landen, M., Hogberg, P., Thase, M. E. 2005 Incidence of sexual side effects in refractory depression during treatment with citaloprarn or paroxetine. J C1in Psychiatry, 66, 100-106. [3] Montejo-Gonzalez, A. L., Llorca, G., Izquierdo, J. A., Ledesma, A., Bousono, M., Ca1cedo, A., Carrasco, J. L., Ciudad, J., Daniel, E., De 1a Gandara, J., Derecho, J., Franco, M., Gomez, M. J., Macias, J. A., Martin, T., Perez, Sanchez, J. M., Sanchez, S., & Vicens, E. 1997 SSRI-induced sexual dysfunction: F1uoxetine, paroxetine, sertra1ine, and fluvoxamine in a prospective, multicenter, and descriptive study of 344 patients. J Sex Marital Ther, 23, 176-194
v.,
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1P.2.c.0241 Association study between BDNF genetic polymorphism and treatment responses of SSRI in major depressive disorder Y. Lee 1 ., Y. Jung1, 1. Park1 , S. Kim 1 , 1. Kim 1, C. Kang 1 , B. Lee 1 , D. Lee2 . 1Pusan National University Hospital, Department of Psychiatry, Busan, South-Korea; 2 Good Gangan General Hospital, Department ofPsychiatry, Busan, South-Korea Background: brain-derived neurotrophic factor (BDNF) is recognized as playing an important role in the survival, differentiation, and outgrowth of select peripheral and central neurons during development and in adulthood. Recent studies suggest that BDNF may playa critical role in both mechanism of antidepressant action and the pathophysiology of major depressive disorder (MDD). The aim of this study is to evaluate whether the BDNF-gene Val66Met polymorphism is associated with susceptibility ofMDD, and antidepressant response in a Korean population. Methods: One hundred thirty-seven patients with MDD and 91 control subjects were recruited and analyzed for this study. Psychiatric diagnoses were carried out using the Korean version of the Structured Clinical Interview for DSM-IV Axis-I disorder (SCIDIV). The severity of depression was measured using the 17-item Hamilton Rating Scale for Depression (HAM-D-17) for MDD patients before and after a 6-week treatment with the antidepressant, Selective Serotonin Reuptake Inhibitor. A minimum baseline HAM-D-17 score of 15 was required for study inclusion. Treatment outcome was measured as response (~50% improvement on HAM-D-17) and remission (final HAM-D-17 ~7). Ninetyone healthy controls were matched by age, sex and education. Control subjects were non-smokers, were not on medication and had no history of major psychiatric disorders, dementia, mental retardation, cancer or tumor and no such disorders in their firstdegree relatives. Five milliliters of blood were withdrawn from each subject by venipuncture into an ethylene diarnine tetraactic acid(EDTA) vacuum tube for DNA analyses. The genotypes of BDNF Val66Met polymorphism in all subject were determined using polymerase chain reaction(PCR). All the assays were performed blind to the subject's status. we examined the association of the BDNF-gene Val66Met polymorphism and therapeutic response in 137 MDD patients who received a 6-week Selective Serotonin Reuptake Inhibitor(SSRI) treatment. Results: There were no significant differences in age and gender distribution between the MDD and control groups. Both samples were found to be Hardy-Weinberg equilibrium (MDD X,2=0.125, df= 1, p=0.723; Control )(2=0.093, df= 1, p=0.759). The genotype or allele frequency of the BDNF polymorphism did not differ significantly between the MDD and control subjects()(2=0.635, df=2, p=0.728). No significant differences were noted in the three-genotype MDD groups (ValNal, VallMet, Met/Met) between responders and non-responders. However, heterozygous patients (VallMet) in comparison to homozygous analogs (ValNal or Met/Met) in BDNF polymorphism tended to have more improved 6-week antidepressant response(p = 0.053). In addition, higher total HAM-D-score percentage change after 6 weeks of antidepressant medication was demonstrated for the heterozygote patients in comparison to homozygous analogs(p = 0.006). Conclusion: This finding suggests the BDNF polymorphism is associated with improved therapeutic SSRI response for patients bearing the BDNF VallMet heterozygote in comparison to the homozygous analogs(ValNal or Met/Met). Nevertheless, the pos-
S418
P.2.c Affective disorders and antidepressants - Antidepressants (clinical)
sibility of false positive findings suggests that further studies are necessary to replicate the findings. References
[1] Choi MJ, Kang RH, Lim Sw, Dh KS, Lee MS. 2006 Brain-derived neurotrophic factor gene polymorphism (Va166Met) and citalopram response in major depressive disorder. Brain Res. 1118:176-182. [2] Tsai SJ, Cheng CY, Yu Yw, Chen TJ, Hong CI 2003 Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet. 123:19-22. [3] Hashimoto K, Shimizu E, Iyo M. 2004 Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev. 45:104-114.
1P.2.C.0251 Early pain response associated with better outcome in emotional symptoms in depressive patients treated with duloxetine E. Schneider1 ., U. Heger12 , M. Linden3 , D. Quail4 , T. Wagner1, H.P. Hundemer1 . 1Lilly Deutschland GmbH, Medical Department, Bad Homburg, Germany; 2 University of Leipzig, Department ofPsychiatry, Leipzig, Germany; 3 Charite University Medicine, Research Group Psychosomatic Rehabilitation, Berlin, Germany; 4Eli Lilly and Co Ltd, European Medical Information Sciences, Windlesham, United Kingdom Purpose: Primary research objective of this observational study was to investigate the association of the change of painful physical symptoms (PPS) during the first 4 weeks, with long-term treatment outcomes of emotional symptoms of depression in patients treated with du10xetine (DLX) in clinical practice. Design and Methods: Multicenter, prospective, 6-month observational study in adult outpatients with a depressive episode (according to ICD-lO) at 693 centers in Germany, starting treatment with DLX. Depression severity was assessed by the clinicianrated 'Inventory for Depressive Symptomatology' (IDS-C) scale, and 'Kurz-Skala Stimmung/Aktivierung' (KUSTA), comprising the items mood, activity, tension/relaxation and sleep; each rated on a visual analog scale (VAS) by the patients. Somatic symptoms and PPS were assessed using the self-rated 'Somatic Symptom Inventory' (SSI) and VAS for pain items. To investigate the association of the change of PPS with outcomes of emotional symptoms, the mean of the KUSTA items and achievement of a 50% reduction in the total IDS-C score at the final visit were analyzed using linear and logistic regression models, respectively. Results: Of the 4,517 patients enrolled (mean age 52.2 years, 71.8% female), 3,320 patients (73.5%) completed the study. The majority ofthe depressed patient population (80.0%) had moderate to severe overall pain (VAS >30mm) at baseline (BL). During DLX treatment, the IDS-C total score (mean (SD)) decreased from BL to 6 months from 39.2 (12.4) to 16.1 (11.9) and the mean KUSTA score increased from 25.2 (16.8) to 58.9 (25.9), both scales indicating improvement of emotional symptoms. The SSI total score (mean (SD)) decreased from 2.47 (0.69) to 1.72 (0.65) and the VAS overall pain from 55.0mm (26.6mm) to 30.5 mm (25.4 mm), indicating improvement of somatic symptoms and PPS. A clinically relevant pain reduction (VAS) of ~30% and ~50% was reported by 61.9% and 48.1% of the patients, respectively. The linear regression analysis of the mean KUSTA score showed that a 50% reduction in overall pain VAS during the first 4 weeks, of the variables tested, had the strongest association with the mean KUSTA score at 6 months. This effect was estimated
to be 13.32 [95%CI 11.24-15.39] points on the KUSTA, which indicates that patients with a ~50% pain reduction after 4 weeks, on average, had a 13.32 point higher mean KUSTA score after 6 months, compared to patients without a ~50% reduction in overall pain. Also, a 50% reduction in overall pain VAS during the first 2 weeks was identified as having a statistically significant effect on the mean KUSTA score at 6 months. For patients with a ~50% reduction in their overall pain VAS during the first 4 weeks, the chance of achieving a 50% reduction in the IDS-C total score after 6 months was 3.00 times higher (95%CI 2.41-3.75) than for those who did not. No unexpected adverse events were found in this naturalistic study. Conclusions: This observational study found a strong association between an early pain response and an improved long-term outcome in emotional symptoms of depression in patients treated with DLX in clinical practice. Research was funded by Lilly Deutschland GmbH, Bad Homburg, Germany.
1P.2.c.0261 Superior antidepressant efficacy of agomelatine vs f1uoxetine in severe major depressive disorder patients: a randomised, double-blind study A. Hale 1 ., R. Corral2 , O. Mencacci3 , J. Saiz Ruiz'l, C. Albarran 1 Sf Martin Hospital, Eastern Sever05 , V. Gentil6 . and Costal Headquarters, Kent, United Kingdom; 2 Centro de Neuropsiquiatria, Neuropsiquiatria, Buenos Aires, Argentina; 3Azienda Ospedaliera Fatebenefratelli e Oftalmico, Salute Mentale, Milano, Italy; 4 Hospital Ramon Y Cajal, Psiquiatria, Madrid, Spain; 5Institut de recherches internationales Servier, Neuro-psychiatry, Courbevoie, France; 6 Instituto de Psiquiatria do Hospital das Clinicas, Psiquiatria, Silo Paulo, Brazil
s
Aim: Agomelatine is a new antidepressant offering a uuique approach to the management of depressive disorders, through its action as a MTlIMT2 receptors' agonist and a 5-HT2C receptor' antagonist. Its efficacy in Major Depressive Disorder (MDD) has been evidenced in several clinical trials, including one in severely depressed patients [1--4]. The aim ofthis study was to demonstrate agomelatine's superiority over fluoxetine, in severely depressed outpatients. Methods: A multinational, multicentric, randomised, doubleblind, parallel groups comparative study of agomelatine 25mg/50mg versus fluoxetine 20mg/40mg for 8-weeks of treatment, with the possibility for blind dose-adjustments respectively at W2 or at W4, in out-patients with a current severe episode of Major Depressive Disorder according to DSM-IV-TR criteria. Severity was defined by HAM-D17 total score equal or greater than 25, combined with a CGI severity of illness score equal or greater than 4. The primary efficacy criteria was the HAM-D17 total score (comparison of the change from baseline to last post-baseline value over the 8-week period between agomelatine and fluoxetine). A stepwise strategy was set-up concerning the main analysis. First the non-inferiority of agomelatine relative to fluoxetine, then in case of a significant non-inferiority test, the superiority of agomelatine versus fluoxetine was studied. These two analyses were carried out in the FAS on the change from baseline to last post-baseline value over the 8-week period, using a two-way