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C.04.01 An innovative pharmacological response to unmet needs
C.04. Innovation in the treatment of depression: a great leap forward switching from one atypical antipsychotic to another is 30−50% in a given year.2 Distinguishing whether the indication for switching is primarily for efficacy or tolerability is clinically useful since the risk-benefits assessments differ in these scenarios. Current treatment guidelines advise waiting four to six weeks before making major changes in antipsychotic treatment. Switching may not be the only option in optimising treatment. A persistent question has been what duration of trial is actually sufficient to assess the likely treatment response outcomes. A lack of a significant time-treatment effect has been noted with antipsychotic effectiveness.3 Thus if nonresponders could be identified shortly after treatment initiation, treatment could be optimised early, which could include dose increase, adding another agent, or switching to potentially more effective treatment alternatives. With confirmation of the early onset of action of antipsychotic (the largest antipsychotic treatment responses are observed in the first month of treatment3), a review of early predictors of response and a discussion of the implications for switching is warranted as is the amount of nonresponse shortly after initiation of antipsychotic treatment and whether it predicts nonresponse at future time points. The differences between early responders and early nonresponders and how these differences may impact remission is of interest. References [1] Lieberman JA, et al., 2005, N Engl J Med 353: 1209−23. [2] Weiden PJ, 2006, Postgrad Med Spec No: 27−44. [3] Leucht S, et al., 2005, Biol Psychiatry 57: 1543–1549.
C.03.03 Culture and the prediction of course and outcome of schizophrenia N. Sartorius1 ° . 1 University of Geneva, Department of Psychiatry, Geneva, Switzerland Studies carried out by the World Health Organization showed that persons with schizophrenia living in developing countries have a more favourable course and outcome of their disease than similar persons with schizophrenia living in developed countries. The numbers of those who were still in the initial episode of the illness were lesser and their social adjustment was continuously improving. Those who did not fully recover had fewer symptoms and the levels of their impairment were less serious. Reports from developing countries also showed that drug-naive patients with schizophrenia have extrapyramidal symptoms when they first contact health care services. These findings exemplify the fact that cross-cultural differences may be of major importance in international, collaborative, multisite efficacy trials.1 Therefore, the impact of cultural differences in terms of early predictors needs to be addressed. These differences alter the ability to predict the course and outcome of schizophrenia. Yet, these differences are rarely taken into account or reported in papers describing the impact of treatment of severe mental illness. A dialogue ought to be held to describe the course and outcome of schizophrenia in groups of patients living in different countries and cultures to examine differences in the predictive power of patient characteristics and the minimal requirements to be respected in pooling data obtained from sites in different countries. References [1] Hopper K, Harrison G, Janca A, and Sartorius N. Recovery from Schizophrenia. Oxford, UK; Oxford University Press. 2007.
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C.04. Innovation in the treatment of depression: a great leap forward C.04.01 An innovative pharmacological response to unmet needs P. Gorwood1 ° . 1 Hopital Louis Mourier, INSERM U675, Colombes Cedex, France Most available antidepressants with different pharmacological profiles, such as inhibitors of serotonin reuptake (SSRIs) or norepinephrine reuptake (NRIs) or both (SNRIs), have limitations that lead some patients to drop out of treatment. Major depressive disorders have been linked to circadian rhythm disturbances for more than 20 years. Life events that disrupt social routines lead to changes in endogenous circadian rhythms in every individual. These changes are experienced as somatic symptoms and, in individuals vulnerable to mood disorders, the circadian system does not re-regulate easily, which may trigger depressive episodes. This consideration has led to the synthesis of agomelatine, a novel melatonergic antidepressant combining melatonergic MT1 and MT2 agonism with serotonergic 5-HT2C antagonism. These three receptors are present at high density in the suprachiasmatic nucleus and are all involved in circadian rhythm regulation. The antidepressant effects of agomelatine have been investigated in animal models, including chronic mild stress, the forced swimming test, learned helplessness, transgenic mice with downregulation of glucocorticoid receptors and psychosocial stress. An antidepressant-like effect of agomelatine was seen in all models. A resynchronizing activity of agomelatine was seen in animal models for delayed sleep phase syndrome, as well as in several original models of circadian disturbance, such as rodents infected by trypanosome or old hamsters. This activity of agomelatine on circadian rhythms was further confirmed in humans, and several randomized, double-blind, placebo-controlled and comparator-controlled studies of the treatment of major depressive disorder indicate that agomelatine is effective and well tolerated. C.04.02 Innovation translates into antidepressant effectiveness G. Goodwin1 ° . 1 University of Oxford, Department of Psychiatry, Headington Oxford, United Kingdom Unipolar depression is a major cause of disability in developed societies. There is significant unmet need because existing treatments are neither as effective nor as free of adverse effects as we would hope. Agomelatine is a new antidepressant with a novel profile of pharmacological action: it is the first melatonergic antidepressant with melatonergic MT1 and MT2 receptor agonist and 5-HT2C receptor antagonist properties. Its efficacy in major depressive disorder has been demonstrated in three pivotal short-term, placebo-controlled trials and in direct head-to-head comparison with existing products, such as sertraline or venlafaxine. The pooling of data from the three agomelatine short-term studies allows analysis of subgroups within the study populations. There is a trend for a larger effect size to be seen with more severely ill patients as a consequence of placebo responses falling. Efficacy is also demonstrated in the maintenance of effect seen after clinical response in a recently completed relapse prevention study, analyzed initially after 6 months. What is unusual, certainly
C.03.03 Culture and the prediction of course and outcome of schizophrenia N. Sartorius1 ° . 1 University of Geneva, Department of Psychiatry, Geneva, Switzerland Studies carried out by the World Health Organization showed that persons with schizophrenia living in developing countries have a more favourable course and outcome of their disease than similar persons with schizophrenia living in developed countries. The numbers of those who were still in the initial episode of the illness were lesser and their social adjustment was continuously improving. Those who did not fully recover had fewer symptoms and the levels of their impairment were less serious. Reports from developing countries also showed that drug-naive patients with schizophrenia have extrapyramidal symptoms when they first contact health care services. These findings exemplify the fact that cross-cultural differences may be of major importance in international, collaborative, multisite efficacy trials.1 Therefore, the impact of cultural differences in terms of early predictors needs to be addressed. These differences alter the ability to predict the course and outcome of schizophrenia. Yet, these differences are rarely taken into account or reported in papers describing the impact of treatment of severe mental illness. A dialogue ought to be held to describe the course and outcome of schizophrenia in groups of patients living in different countries and cultures to examine differences in the predictive power of patient characteristics and the minimal requirements to be respected in pooling data obtained from sites in different countries. References [1] Hopper K, Harrison G, Janca A, and Sartorius N. Recovery from Schizophrenia. Oxford, UK; Oxford University Press. 2007.
S591
C.04. Innovation in the treatment of depression: a great leap forward C.04.01 An innovative pharmacological response to unmet needs P. Gorwood1 ° . 1 Hopital Louis Mourier, INSERM U675, Colombes Cedex, France Most available antidepressants with different pharmacological profiles, such as inhibitors of serotonin reuptake (SSRIs) or norepinephrine reuptake (NRIs) or both (SNRIs), have limitations that lead some patients to drop out of treatment. Major depressive disorders have been linked to circadian rhythm disturbances for more than 20 years. Life events that disrupt social routines lead to changes in endogenous circadian rhythms in every individual. These changes are experienced as somatic symptoms and, in individuals vulnerable to mood disorders, the circadian system does not re-regulate easily, which may trigger depressive episodes. This consideration has led to the synthesis of agomelatine, a novel melatonergic antidepressant combining melatonergic MT1 and MT2 agonism with serotonergic 5-HT2C antagonism. These three receptors are present at high density in the suprachiasmatic nucleus and are all involved in circadian rhythm regulation. The antidepressant effects of agomelatine have been investigated in animal models, including chronic mild stress, the forced swimming test, learned helplessness, transgenic mice with downregulation of glucocorticoid receptors and psychosocial stress. An antidepressant-like effect of agomelatine was seen in all models. A resynchronizing activity of agomelatine was seen in animal models for delayed sleep phase syndrome, as well as in several original models of circadian disturbance, such as rodents infected by trypanosome or old hamsters. This activity of agomelatine on circadian rhythms was further confirmed in humans, and several randomized, double-blind, placebo-controlled and comparator-controlled studies of the treatment of major depressive disorder indicate that agomelatine is effective and well tolerated. C.04.02 Innovation translates into antidepressant effectiveness G. Goodwin1 ° . 1 University of Oxford, Department of Psychiatry, Headington Oxford, United Kingdom Unipolar depression is a major cause of disability in developed societies. There is significant unmet need because existing treatments are neither as effective nor as free of adverse effects as we would hope. Agomelatine is a new antidepressant with a novel profile of pharmacological action: it is the first melatonergic antidepressant with melatonergic MT1 and MT2 receptor agonist and 5-HT2C receptor antagonist properties. Its efficacy in major depressive disorder has been demonstrated in three pivotal short-term, placebo-controlled trials and in direct head-to-head comparison with existing products, such as sertraline or venlafaxine. The pooling of data from the three agomelatine short-term studies allows analysis of subgroups within the study populations. There is a trend for a larger effect size to be seen with more severely ill patients as a consequence of placebo responses falling. Efficacy is also demonstrated in the maintenance of effect seen after clinical response in a recently completed relapse prevention study, analyzed initially after 6 months. What is unusual, certainly