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P.2.c.015 Effect of mirtazapine for insomnia in patients with major depressive episode: a polysomnographic study
S320
P.2.c Affective disorders and antidepressants – Antidepressants (clinical)
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 SH, 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.
physicians still did not prescribe the required dosage. Also, general practitioners as well as psychiatrists did not prescribe the standard dosis. Guideline exposure can result in lower treatment effects as it leads to higher dosages in milder forms of depression, which are the majority of outpatients. Physicians are intelligent non-compliers. Non-compliance of physicians with prescribing guidelines must therefore lead to research on the reasons before guidelines should be enforced. Guidelines must be evidenced based not only by referring to literature reviews but by testing their clinical effects in controlled clinical trials. This can be done by randomized controlled comparisons of guideline exposed and guideline naive physicians.
P.2.c.014 A randomized controlled clinical trial comparing “guideline exposed” and “guideline naive” physicians in respect to dosage selection and treatment outcome with doxepin
P.2.c.015 Effect of mirtazapine for insomnia in patients with major depressive episode: a polysomnographic study
M. Linden ° . Charit´e University Medicine, Research Group Psychosomatic Rehabilitation, Berlin, Germany
H. Kim ° , K.J. Lee, S.H. Lee. Ilsan Paik Hospital, Inje University, Neuropsychiatry, Goyang, Republic of Korea
Background: 150 mg/d are recommended as standard dosage for treatment with tricyclic antidepressants but studies have shown that in daily practice physicians regularly prescribe lower dosages. It has been argued that this is a reason for insufficient treatment outcome, that this can be explained by a lack of knowledge of the physicians and that guidelines can help to improve the quality of medical care. The empirical question is, whether physicians who have been exposed to guidelines on prescribing will follow the given recommendations and whether this will lead to a better treatment outcome. Methods: 161 general practitioners and 162 psychiatrists in private practice documented 1319 patients whom they prescribed doxepin for individual clinical reasons. Physicians were randomly divided into an intervention group (158 guideline exposed physicians) that received extensive information about prescribing guidelines and a control group (165 guideline naive physicians). All physicians were free to treat the individual patient according to their clinical discretion. Prospective and standardized case documentation included sociodemographic data, history, diagnosis, severity of the illness and prescribing pattern. Results: The average dosage was 95 mg/d in the intervention group and 83 mg/d in the control group (F = 19.15; p < 0). Psychiatrists prescribed on average 97.7 mg/d in the intervention group and 83.19 mg/d in the control group, while general practitioners and internists 92.96 mg/d in the intervention and 82.87 in the control group. Dosage levels were not significantly different (F = 0.67, p = 0.41) between general practitioners/internists and psychiatrists. Patients with a CGI rating of “mildly ill” received on average 57.97 mg/d (±44.59), “moderately ill” 73.15 mg/d (±38.97), “distinctly ill” 91.41 mg/d (±46.83), and “severely” and “extreme severely ill” 125.44 mg/d (±53.54). Patients with low dosages (5−74 mg/d) had a better improvement rate (64.8%) than patients treated with middle (75–124 mg/d; 61.3%) or high dosages (125– 350 mg/d; 60.7%) (F = 3.76; p = 0.024) which was especially true for patients with milder forms of depression who had the largest improvement rate (69.9%) when treated with low dosages, as compared to middle (64.9%) or high dosage treatment (45.9%) (F = 3.4; p = 0.032). Guideline exposure resulted in increased daily dosages especially in milder forms of depression and in reduced rates of improvement. Conclusion: Lack of knowledge can not explain the regular low dosage treatment with antidepressants, as guideline exposed
Purpose of the study: Sleep disturbances are a common feature in major depressive disorder patients. About 90% of major depressive disorder patients report sleep problems including difficulties to fall asleep, early morning awakening and daytime fatigue. Polysomnographic study has revealed that dirupted sleep continuity, altered REM sleep and reduced slow wave sleep (SWS) are common in patients with major depressive episode. Some antidepressant medication, for example selective serotonin reuptake inhibitors (SSRIs), has adverse effect on sleep. It has been reported that mirtazapine improves sleep quality in normal sleepers. Some depressed patients report subjective feeling of improved sleep quality after mirtazapine medication. This study was aimed to determine the effect of mirtazapine on the polysomnographic sleep, especially slow wave sleep (SWS) and rapid eye movement (REM) sleep in patients with major depressive episode. Methods: Twenty-one patient, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria (DSM-IV) for a diagnosis of major depressive episode, who reported symptom of sleep disturbances were enrolled in this study. They all had given their consent to take part in study. Patients who presented with any other diagnosis on Axis I of DSM-IV, any decompensated organic disorder (especially neurological), significant alcohol or other substance abuse/dependence (according to DSM-IV criteria) and mental retardation excluded from the study. All laboratory parameters including thyroid function tests must be within normal range. The patients were aged 18 years and over. At a 7 day of wash-out period, they were evaluated with polysomnography. After polysomnography had taken, they had received mirtazapine 15−45 mg per day for the duration of 8 weeks. The dose was adjusted as required, monitoring symptom improvement of their depressed mood. If the patients complained any side effect of mirtazapine, like somnolence and facial edema, the dose was also adjusted. Any other medications, including hypnotics and other antidepressants, were not allowed. After a mean of 8 weeks, they were re-evaluated with polysomnography. All polysomnographic recordings were carried out in the Sleep Research and Laboratory Unit, Ilsan Paik Hospital, Inje University. Results: In total twenty-one subjects fourteen were female and seven subjects were male. Their mean age (±SD) of this group was 39.57±11.99. Mean duration of their depressive illness (±SD) was 1.78±1.24. After 8 weeks of mirtazapine medication,
P.2.c Affective disorders and antidepressants – Antidepressants (clinical) polysomnography in this major depressive disorder group showed decrease in sleep latency (P < 0.001). We also find that the percentage of REM sleep (P < 0.001) was decreased. Stage 1 sleep (P < 0.001) was also decrease. On the other hand, the percentage of slow wave sleep (P < 0.001) was increased. Conclusions: The results suggest that mirtazapine is useful as a treatment for insomnia in patients with major depressive disorder and that it also significantly improves sleep quality. However, more systematic research, including placebo-controlled comparative studies, will be necessary. References [1] Schittecatte M, Dumont F, Machowski R, Cornil C, Lavergne F, Wilmotte J, 2002, Effects of mirtazapine on sleep polygraphic variables in major depression, Neuropsychobiology, 46, 4, 197–201. [2] Aslan S, Isik E, Cosar B, 2002, The effects of mirtazapine on sleep: a placebo controlled, double-blind study in young healthy volunteers, Sleep, Sep 15, 25, 6, 677–679.
P.2.c.016 Antidepressant use and the risk of suicide, attempted suicide and overall mortality in a nation-wide cohort J. Tiihonen1 ° , J. L¨onnqvist2 , K. Wahlbeck3 , T. Klaukka4 , A. Tanskanen2 , J. Haukka2 . 1 University of Kuopio, Department of Forensic Psychiatry, Kuopio, Finland; 2 National Public Health Institute, Department of Mental Health and Alcohol Research, Helsinki, Finland; 3 National Research and Development Centre for Welfare and Health, STAKES, Helsinki, Finland; 4 The Social Insurance Institution of Finland, N/A, Helsinki, Finland Background: It is currently unknown if antidepressant treatment is associated with either increased or decreased risk of suicide. We aimed to estimate the risk of suicide, attempted suicide, and overall mortality during antidepressant treatments in a real-life setting with high statistical power. Method: This was a cohort study in which all subjects without psychosis, hospitalized due to a suicide attempt during the years 1997–2003 in Finland (n = 15,390), were followed up through a nation-wide computerized database (an average follow-up period of 3.4 years). Main outcome measures were the propensity score adjusted relative risks (RR) during mono-therapy with the most frequently used antidepressants (fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, mianserin, mirtazapine, venlafaxine, amitriptyline, and doxepine) compared with no antidepressant treatment. The following information was obtained for all individuals: sex, age at the time of index hospitalization (10−14, 15– 19, 20−30, 30−65, > 65 years), geographical location (22 hospital districts covering whole country), number of antidepressant prescriptions during the previous year before index date (0, 1−2, >2), the number of severe suicide attempts leading to hospitalizations during 5 years prior to index hospitalization (0, 1, 2, 3–4, > 4), date of index hospitalization, number of hospitalizations due to attempted suicide (1, 2, 3, 4−6, > 6), and usage of antidepressant medications after index hospitalization. The duration of the antidepressant treatment was calculated according to the purchased DDDs. Cox proportional hazards analyses with counting process approach were conducted using the outcome variables mentioned above. Since those patients who never used antidepressant during follow-up may differ from those who did, we also analyzed the risk of attempted suicide, completed suicide, and death among patients who had never used antidepressants, those who had stopped using medication, and those who were currently using medication.
S321
Results: A total of 602 suicides, 7136 suicide attempts and 1583 deaths were recorded during the follow-up period. In the entire cohort, fluoxetine use was associated with the lowest risk (RR 0.52, 0.30–0.93), and venlafaxine use with the highest risk (RR 1.61, 1.01–2.57) of suicide. A substantially lower mortality was observed during SSRI use (RR 0.59, 0.49–0.71; p < 0.001), and this was attributable to a decrease in cardiovascular and cerebrovascular deaths (RR 0.42, 0.24–0.71, p = 0.001). Among subjects who had ever used any antidepressant, the current use of medication was associated with a markedly increased risk of attempted suicide (+39%, p < 0.001), but also with a markedly decreased risk of completed suicide (−32%, p = 0.002), and mortality (−49%, p < 0.001) when compared with no current use of medication. The results for subjects aged 10–19 years were basically the same as those in the total population, except for an increased risk of death with paroxetine (RR 5.44, 2.15–13.7, p < 0.001). Conclusions: Among suicidal subjects who had ever used antidepressants, the current use of any antidepressant was associated with a markedly increased risk of attempted suicide and, at the same time, with markedly decreased risk of completed suicide, and death. Lower mortality was attributable to a decrease in cardiovascular and cerebrovascular deaths during SSRI use. References [1] Tiihonen J., Lonnqvist J., Wahlbeck K., Klaukka T., Tanskanen A., Haukka J., 2006, Antidepressants and the risk of suicide, attempted suicide and overall mortality in a nation-wide cohort, Arch Gen Psychiatry, in press.
P.2.c.017 Antidepressant efficacy of agomelatine in major depressive disorder: meta-analysis of three pivotal studies S.A. Montgomery1 ° , J.P. Olie2 , S.H. Kennedy3 . 1 University of London, Imperial College School of Medicine, London, United Kingdom; 2 Sainte Anne Hospital, Psychiatry, Paris, France; 3University Health Network, Psychiatry, Toronto, Canada Aim: Agomelatine an agonist of melatonergic MT1/MT2 receptors with 5HT2C antagonist properties, has proven its efficacy in three pivotal placebo-controlled trials in Major Depressive Disorders (MDD) both in the overall and in the severe subpopulations [1−3]. The aim of the present study is to present an analysis of the pooled data of these studies to increase the statistical power to investigate efficacy in the overall as well as in the severe subpopulation. Methods: In the first study, agomelatine was administered at a dose of 25 mg for 8 weeks using paroxetine (20 mg) as internal validator. The other two studies used a flexible design: patients received agomelatine 25 mg for six weeks and those with insufficient improvement after two weeks, had their agomelatine dose raised to 50 mg. The criteria for dose increase were defined prior to the study start and were blind to both the investigators and patients. The primary efficacy criterion for the 3 studies was the 17–item Hamilton Rating scale for depression (HAMD) on the Intention-to-treat (ITT) population using the last observation carried forward (LOCF). Secondary measures included clinical global impression scales (CGI) and percentage of responders. The antidepressant efficacy of agomelatine 25/50 mg was illustrated by the meta-analysis of these pooled data. Severe subpopulations of these studies were also analysed, using a score of 25 or more
P.2.c Affective disorders and antidepressants – Antidepressants (clinical)
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 SH, 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.
physicians still did not prescribe the required dosage. Also, general practitioners as well as psychiatrists did not prescribe the standard dosis. Guideline exposure can result in lower treatment effects as it leads to higher dosages in milder forms of depression, which are the majority of outpatients. Physicians are intelligent non-compliers. Non-compliance of physicians with prescribing guidelines must therefore lead to research on the reasons before guidelines should be enforced. Guidelines must be evidenced based not only by referring to literature reviews but by testing their clinical effects in controlled clinical trials. This can be done by randomized controlled comparisons of guideline exposed and guideline naive physicians.
P.2.c.014 A randomized controlled clinical trial comparing “guideline exposed” and “guideline naive” physicians in respect to dosage selection and treatment outcome with doxepin
P.2.c.015 Effect of mirtazapine for insomnia in patients with major depressive episode: a polysomnographic study
M. Linden ° . Charit´e University Medicine, Research Group Psychosomatic Rehabilitation, Berlin, Germany
H. Kim ° , K.J. Lee, S.H. Lee. Ilsan Paik Hospital, Inje University, Neuropsychiatry, Goyang, Republic of Korea
Background: 150 mg/d are recommended as standard dosage for treatment with tricyclic antidepressants but studies have shown that in daily practice physicians regularly prescribe lower dosages. It has been argued that this is a reason for insufficient treatment outcome, that this can be explained by a lack of knowledge of the physicians and that guidelines can help to improve the quality of medical care. The empirical question is, whether physicians who have been exposed to guidelines on prescribing will follow the given recommendations and whether this will lead to a better treatment outcome. Methods: 161 general practitioners and 162 psychiatrists in private practice documented 1319 patients whom they prescribed doxepin for individual clinical reasons. Physicians were randomly divided into an intervention group (158 guideline exposed physicians) that received extensive information about prescribing guidelines and a control group (165 guideline naive physicians). All physicians were free to treat the individual patient according to their clinical discretion. Prospective and standardized case documentation included sociodemographic data, history, diagnosis, severity of the illness and prescribing pattern. Results: The average dosage was 95 mg/d in the intervention group and 83 mg/d in the control group (F = 19.15; p < 0). Psychiatrists prescribed on average 97.7 mg/d in the intervention group and 83.19 mg/d in the control group, while general practitioners and internists 92.96 mg/d in the intervention and 82.87 in the control group. Dosage levels were not significantly different (F = 0.67, p = 0.41) between general practitioners/internists and psychiatrists. Patients with a CGI rating of “mildly ill” received on average 57.97 mg/d (±44.59), “moderately ill” 73.15 mg/d (±38.97), “distinctly ill” 91.41 mg/d (±46.83), and “severely” and “extreme severely ill” 125.44 mg/d (±53.54). Patients with low dosages (5−74 mg/d) had a better improvement rate (64.8%) than patients treated with middle (75–124 mg/d; 61.3%) or high dosages (125– 350 mg/d; 60.7%) (F = 3.76; p = 0.024) which was especially true for patients with milder forms of depression who had the largest improvement rate (69.9%) when treated with low dosages, as compared to middle (64.9%) or high dosage treatment (45.9%) (F = 3.4; p = 0.032). Guideline exposure resulted in increased daily dosages especially in milder forms of depression and in reduced rates of improvement. Conclusion: Lack of knowledge can not explain the regular low dosage treatment with antidepressants, as guideline exposed
Purpose of the study: Sleep disturbances are a common feature in major depressive disorder patients. About 90% of major depressive disorder patients report sleep problems including difficulties to fall asleep, early morning awakening and daytime fatigue. Polysomnographic study has revealed that dirupted sleep continuity, altered REM sleep and reduced slow wave sleep (SWS) are common in patients with major depressive episode. Some antidepressant medication, for example selective serotonin reuptake inhibitors (SSRIs), has adverse effect on sleep. It has been reported that mirtazapine improves sleep quality in normal sleepers. Some depressed patients report subjective feeling of improved sleep quality after mirtazapine medication. This study was aimed to determine the effect of mirtazapine on the polysomnographic sleep, especially slow wave sleep (SWS) and rapid eye movement (REM) sleep in patients with major depressive episode. Methods: Twenty-one patient, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria (DSM-IV) for a diagnosis of major depressive episode, who reported symptom of sleep disturbances were enrolled in this study. They all had given their consent to take part in study. Patients who presented with any other diagnosis on Axis I of DSM-IV, any decompensated organic disorder (especially neurological), significant alcohol or other substance abuse/dependence (according to DSM-IV criteria) and mental retardation excluded from the study. All laboratory parameters including thyroid function tests must be within normal range. The patients were aged 18 years and over. At a 7 day of wash-out period, they were evaluated with polysomnography. After polysomnography had taken, they had received mirtazapine 15−45 mg per day for the duration of 8 weeks. The dose was adjusted as required, monitoring symptom improvement of their depressed mood. If the patients complained any side effect of mirtazapine, like somnolence and facial edema, the dose was also adjusted. Any other medications, including hypnotics and other antidepressants, were not allowed. After a mean of 8 weeks, they were re-evaluated with polysomnography. All polysomnographic recordings were carried out in the Sleep Research and Laboratory Unit, Ilsan Paik Hospital, Inje University. Results: In total twenty-one subjects fourteen were female and seven subjects were male. Their mean age (±SD) of this group was 39.57±11.99. Mean duration of their depressive illness (±SD) was 1.78±1.24. After 8 weeks of mirtazapine medication,
P.2.c Affective disorders and antidepressants – Antidepressants (clinical) polysomnography in this major depressive disorder group showed decrease in sleep latency (P < 0.001). We also find that the percentage of REM sleep (P < 0.001) was decreased. Stage 1 sleep (P < 0.001) was also decrease. On the other hand, the percentage of slow wave sleep (P < 0.001) was increased. Conclusions: The results suggest that mirtazapine is useful as a treatment for insomnia in patients with major depressive disorder and that it also significantly improves sleep quality. However, more systematic research, including placebo-controlled comparative studies, will be necessary. References [1] Schittecatte M, Dumont F, Machowski R, Cornil C, Lavergne F, Wilmotte J, 2002, Effects of mirtazapine on sleep polygraphic variables in major depression, Neuropsychobiology, 46, 4, 197–201. [2] Aslan S, Isik E, Cosar B, 2002, The effects of mirtazapine on sleep: a placebo controlled, double-blind study in young healthy volunteers, Sleep, Sep 15, 25, 6, 677–679.
P.2.c.016 Antidepressant use and the risk of suicide, attempted suicide and overall mortality in a nation-wide cohort J. Tiihonen1 ° , J. L¨onnqvist2 , K. Wahlbeck3 , T. Klaukka4 , A. Tanskanen2 , J. Haukka2 . 1 University of Kuopio, Department of Forensic Psychiatry, Kuopio, Finland; 2 National Public Health Institute, Department of Mental Health and Alcohol Research, Helsinki, Finland; 3 National Research and Development Centre for Welfare and Health, STAKES, Helsinki, Finland; 4 The Social Insurance Institution of Finland, N/A, Helsinki, Finland Background: It is currently unknown if antidepressant treatment is associated with either increased or decreased risk of suicide. We aimed to estimate the risk of suicide, attempted suicide, and overall mortality during antidepressant treatments in a real-life setting with high statistical power. Method: This was a cohort study in which all subjects without psychosis, hospitalized due to a suicide attempt during the years 1997–2003 in Finland (n = 15,390), were followed up through a nation-wide computerized database (an average follow-up period of 3.4 years). Main outcome measures were the propensity score adjusted relative risks (RR) during mono-therapy with the most frequently used antidepressants (fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, mianserin, mirtazapine, venlafaxine, amitriptyline, and doxepine) compared with no antidepressant treatment. The following information was obtained for all individuals: sex, age at the time of index hospitalization (10−14, 15– 19, 20−30, 30−65, > 65 years), geographical location (22 hospital districts covering whole country), number of antidepressant prescriptions during the previous year before index date (0, 1−2, >2), the number of severe suicide attempts leading to hospitalizations during 5 years prior to index hospitalization (0, 1, 2, 3–4, > 4), date of index hospitalization, number of hospitalizations due to attempted suicide (1, 2, 3, 4−6, > 6), and usage of antidepressant medications after index hospitalization. The duration of the antidepressant treatment was calculated according to the purchased DDDs. Cox proportional hazards analyses with counting process approach were conducted using the outcome variables mentioned above. Since those patients who never used antidepressant during follow-up may differ from those who did, we also analyzed the risk of attempted suicide, completed suicide, and death among patients who had never used antidepressants, those who had stopped using medication, and those who were currently using medication.
S321
Results: A total of 602 suicides, 7136 suicide attempts and 1583 deaths were recorded during the follow-up period. In the entire cohort, fluoxetine use was associated with the lowest risk (RR 0.52, 0.30–0.93), and venlafaxine use with the highest risk (RR 1.61, 1.01–2.57) of suicide. A substantially lower mortality was observed during SSRI use (RR 0.59, 0.49–0.71; p < 0.001), and this was attributable to a decrease in cardiovascular and cerebrovascular deaths (RR 0.42, 0.24–0.71, p = 0.001). Among subjects who had ever used any antidepressant, the current use of medication was associated with a markedly increased risk of attempted suicide (+39%, p < 0.001), but also with a markedly decreased risk of completed suicide (−32%, p = 0.002), and mortality (−49%, p < 0.001) when compared with no current use of medication. The results for subjects aged 10–19 years were basically the same as those in the total population, except for an increased risk of death with paroxetine (RR 5.44, 2.15–13.7, p < 0.001). Conclusions: Among suicidal subjects who had ever used antidepressants, the current use of any antidepressant was associated with a markedly increased risk of attempted suicide and, at the same time, with markedly decreased risk of completed suicide, and death. Lower mortality was attributable to a decrease in cardiovascular and cerebrovascular deaths during SSRI use. References [1] Tiihonen J., Lonnqvist J., Wahlbeck K., Klaukka T., Tanskanen A., Haukka J., 2006, Antidepressants and the risk of suicide, attempted suicide and overall mortality in a nation-wide cohort, Arch Gen Psychiatry, in press.
P.2.c.017 Antidepressant efficacy of agomelatine in major depressive disorder: meta-analysis of three pivotal studies S.A. Montgomery1 ° , J.P. Olie2 , S.H. Kennedy3 . 1 University of London, Imperial College School of Medicine, London, United Kingdom; 2 Sainte Anne Hospital, Psychiatry, Paris, France; 3University Health Network, Psychiatry, Toronto, Canada Aim: Agomelatine an agonist of melatonergic MT1/MT2 receptors with 5HT2C antagonist properties, has proven its efficacy in three pivotal placebo-controlled trials in Major Depressive Disorders (MDD) both in the overall and in the severe subpopulations [1−3]. The aim of the present study is to present an analysis of the pooled data of these studies to increase the statistical power to investigate efficacy in the overall as well as in the severe subpopulation. Methods: In the first study, agomelatine was administered at a dose of 25 mg for 8 weeks using paroxetine (20 mg) as internal validator. The other two studies used a flexible design: patients received agomelatine 25 mg for six weeks and those with insufficient improvement after two weeks, had their agomelatine dose raised to 50 mg. The criteria for dose increase were defined prior to the study start and were blind to both the investigators and patients. The primary efficacy criterion for the 3 studies was the 17–item Hamilton Rating scale for depression (HAMD) on the Intention-to-treat (ITT) population using the last observation carried forward (LOCF). Secondary measures included clinical global impression scales (CGI) and percentage of responders. The antidepressant efficacy of agomelatine 25/50 mg was illustrated by the meta-analysis of these pooled data. Severe subpopulations of these studies were also analysed, using a score of 25 or more