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C.12.03 Evidence of agomelatine's antidepressant efficacy: the key points
C.12. Paving the way to remission: the melatonergic approach in depression Further investigation into the action of memantine may help in generating more effective therapy for patients with AD, by helping to define the pathological processes underlying symptoms such as agitation.
C.12. Paving the way to remission: the melatonergic approach in depression C.12.01 From circadian rhythms to clock genes in depression F. Turek ° . Northwestern University, Center for Circadian Biology & Medicine, Evanston, USA Depression, particularly unipolar depression, has often been linked to circadian (i.e, about 24-hr) rhythm abnormalities. The observation that many diverse rhythms are disrupted in depressed patients indicates that such disturbances are not unique to specific rhythms, but instead are of a more central origin (i.e. involve the central circadian pacemaker and/or the molecular circadian clock core machinery). One rhythm that is often disrupted in depression is the sleep-wake cycle: a disruption that, in turn, may lead to other rhythm disturbances. Thus, there are two general ways disrupted circadian rhythms could lead to depression: (1) disorganization within the circadian system could itself lead to neurobiological dysfunction, and/or (2) a circadian disturbance of the normal sleep-wake cycle could facilitate or exacerbate the depressed state. This presentation will discuss evidence indicating that disorganization within the circadian clock system is associated with depression, and that insomnia itself may “cause” depression. The recent discovery of the molecular clock that is responsible for the generation of circadian rhythms provides novel mechanistic insights into how rhythm abnormalties may lead to disrupted behavioral states, and offers new therapeutic avenues for treating timing abnormalties that may underlie depression. The finding that the molecular circadian clock is present in many cells in the CNS, and regulates the timing of the expression of at least 10% of the transcripts in many tissues, emphasizes how circadian dysfunction could have drastic consequences for normal physiological function in the brain. C.12.02 The interaction between the internal clock and antidepressant efficacy G. Racagni ° . University of Milan, university, Milan, Italy The suprachiasmatic nucleus (SCN) in mammals is the biological clock of the organism, the site of the entrainment of circadian rhythms, which receives direct light information through the retinohypothalamic tract. Lesions in the SCN have been shown to disrupt circadian rhythmicity. Melatonergic receptors, MT1 and MT2 , are expressed in high density in the SCN and are directly involved in the regulation of circadian rhythms. Also Serotonergic 5HT2C receptors are found in the SCN, and evidence for their circadian expression and for their role in the regulation of circadian rhythms will be discussed. Depressed patients often have disturbed and disrupted circadian rhythms and therefore an innovative antidepressant therapy might be to interfere with the (disturbed) regulation of circadian rhythms.
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Agomelatine, is the first melatonergic antidepressant with unique pharmacologic properties (an agonist at melatonergic MT1 and MT2 receptors and an antagonist at 5-HT2C receptors) [1,2]. Agomelatine resynchronizes circadian rhythms in models characterized by desynchronized circadian rhythms and shows antidepressant efficacy in several animal models. In microdialysis studies, agomelatine-treated rats showed an increased release of noradrenaline and dopamine in the frontal cortex but not in the nucleus accumbens, and extracellular serotonin levels of serotonin were unaltered. All of this makes agomelatine unique among available antidepressants. We suggest the possible involvement of melatonergic and 5-HT2C receptors, possibly through a synergistic action, in the antidepressant efficacy of agomelatine. References [1] Audinot V, et al, 2003, Naunyn-Schmiedeberg’s Arch Pharmacol 367, 553–561. [2] Millan MJ, et al, year, J Pharmacol Exp Ther 306, 959–964.
C.12.03 Evidence of agomelatine’s antidepressant efficacy: the key points H. M¨oller ° . University of Munich, Department of Psychiatry, Munich, Germany Data from several preclinical (animal) studies and clinical trials in depressed patients demonstrated antidepressant effects for agomelatine, a melatonergic MT1 and MT2 receptor agonist with 5-HT2C receptor antagonistic properties. Agomelatine is the first melatonergic antidepressant and therefore represents a novel approach to the treatment of major depressive disorders. Antidepressant properties of agomelatine, and its favorable tolerability profile, have been demonstrated in several clinical trials. Agomelatine has shown good efficacy in the treatment of major depressed disorders in clinical trials, including large-scale phase III studies either versus placebo or comparators. Efficacy was superior in comparison to placebo and at least equal in comparison to active comparators such as SSRIs and SNRIs. This finding was also true for a subgroup of severely depressed patients across clinical trials, in which the efficacy was incremental with the severity of the depression at baseline. A reduction in sleeprelated complaints, but without any sedation during the daytime, was seen early, from the first week of treatment onwards (improvement of ease of getting to sleep and quality of sleep). Agomelatine was very well tolerated and the rate of treatment-emergent adverse events was always below that seen with SSRIs or SNRIs. The lack of withdrawal symptoms after abrupt discontinuation of treatment clearly represents another important clinical benefit. The clinical development of agomelatine demonstrated its antidepressant efficacy as well as its ability to resynchronize disturbed circadian rhythms in depressed patients. C.12.04 A high quality remission: benefits for depressed patients R. Lam ° . University of British Columbia, Vancouver, Canada There is general consensus that clinical remission is the target for the acute phase of depression treatment, since the presence of residual depressive symptoms is associated with poor prognosis (e.g., greater risk of relapse, chronicity, social impairment, and
C.12. Paving the way to remission: the melatonergic approach in depression C.12.01 From circadian rhythms to clock genes in depression F. Turek ° . Northwestern University, Center for Circadian Biology & Medicine, Evanston, USA Depression, particularly unipolar depression, has often been linked to circadian (i.e, about 24-hr) rhythm abnormalities. The observation that many diverse rhythms are disrupted in depressed patients indicates that such disturbances are not unique to specific rhythms, but instead are of a more central origin (i.e. involve the central circadian pacemaker and/or the molecular circadian clock core machinery). One rhythm that is often disrupted in depression is the sleep-wake cycle: a disruption that, in turn, may lead to other rhythm disturbances. Thus, there are two general ways disrupted circadian rhythms could lead to depression: (1) disorganization within the circadian system could itself lead to neurobiological dysfunction, and/or (2) a circadian disturbance of the normal sleep-wake cycle could facilitate or exacerbate the depressed state. This presentation will discuss evidence indicating that disorganization within the circadian clock system is associated with depression, and that insomnia itself may “cause” depression. The recent discovery of the molecular clock that is responsible for the generation of circadian rhythms provides novel mechanistic insights into how rhythm abnormalties may lead to disrupted behavioral states, and offers new therapeutic avenues for treating timing abnormalties that may underlie depression. The finding that the molecular circadian clock is present in many cells in the CNS, and regulates the timing of the expression of at least 10% of the transcripts in many tissues, emphasizes how circadian dysfunction could have drastic consequences for normal physiological function in the brain. C.12.02 The interaction between the internal clock and antidepressant efficacy G. Racagni ° . University of Milan, university, Milan, Italy The suprachiasmatic nucleus (SCN) in mammals is the biological clock of the organism, the site of the entrainment of circadian rhythms, which receives direct light information through the retinohypothalamic tract. Lesions in the SCN have been shown to disrupt circadian rhythmicity. Melatonergic receptors, MT1 and MT2 , are expressed in high density in the SCN and are directly involved in the regulation of circadian rhythms. Also Serotonergic 5HT2C receptors are found in the SCN, and evidence for their circadian expression and for their role in the regulation of circadian rhythms will be discussed. Depressed patients often have disturbed and disrupted circadian rhythms and therefore an innovative antidepressant therapy might be to interfere with the (disturbed) regulation of circadian rhythms.
S605
Agomelatine, is the first melatonergic antidepressant with unique pharmacologic properties (an agonist at melatonergic MT1 and MT2 receptors and an antagonist at 5-HT2C receptors) [1,2]. Agomelatine resynchronizes circadian rhythms in models characterized by desynchronized circadian rhythms and shows antidepressant efficacy in several animal models. In microdialysis studies, agomelatine-treated rats showed an increased release of noradrenaline and dopamine in the frontal cortex but not in the nucleus accumbens, and extracellular serotonin levels of serotonin were unaltered. All of this makes agomelatine unique among available antidepressants. We suggest the possible involvement of melatonergic and 5-HT2C receptors, possibly through a synergistic action, in the antidepressant efficacy of agomelatine. References [1] Audinot V, et al, 2003, Naunyn-Schmiedeberg’s Arch Pharmacol 367, 553–561. [2] Millan MJ, et al, year, J Pharmacol Exp Ther 306, 959–964.
C.12.03 Evidence of agomelatine’s antidepressant efficacy: the key points H. M¨oller ° . University of Munich, Department of Psychiatry, Munich, Germany Data from several preclinical (animal) studies and clinical trials in depressed patients demonstrated antidepressant effects for agomelatine, a melatonergic MT1 and MT2 receptor agonist with 5-HT2C receptor antagonistic properties. Agomelatine is the first melatonergic antidepressant and therefore represents a novel approach to the treatment of major depressive disorders. Antidepressant properties of agomelatine, and its favorable tolerability profile, have been demonstrated in several clinical trials. Agomelatine has shown good efficacy in the treatment of major depressed disorders in clinical trials, including large-scale phase III studies either versus placebo or comparators. Efficacy was superior in comparison to placebo and at least equal in comparison to active comparators such as SSRIs and SNRIs. This finding was also true for a subgroup of severely depressed patients across clinical trials, in which the efficacy was incremental with the severity of the depression at baseline. A reduction in sleeprelated complaints, but without any sedation during the daytime, was seen early, from the first week of treatment onwards (improvement of ease of getting to sleep and quality of sleep). Agomelatine was very well tolerated and the rate of treatment-emergent adverse events was always below that seen with SSRIs or SNRIs. The lack of withdrawal symptoms after abrupt discontinuation of treatment clearly represents another important clinical benefit. The clinical development of agomelatine demonstrated its antidepressant efficacy as well as its ability to resynchronize disturbed circadian rhythms in depressed patients. C.12.04 A high quality remission: benefits for depressed patients R. Lam ° . University of British Columbia, Vancouver, Canada There is general consensus that clinical remission is the target for the acute phase of depression treatment, since the presence of residual depressive symptoms is associated with poor prognosis (e.g., greater risk of relapse, chronicity, social impairment, and