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C.05.04 Targeting the melatonergic system: a new approach to treat depression
S600
C.05. From circadian rhythm disorders to psychiatric diseases
developed two lines of evidence in support of this hypothesis. We demonstrated that life events characterized by social rhythm disruption are temporally associated with onset of mood episodes, particularly mania, among individuals with a history of bipolar disorder (Malkoff-Schwartz et al, 1998; 2000). We now have demonstrated that a psychotherapeutic intervention for bipolar disorder specifically targeting the regularizing of daily routines is associated with the prevention of both manic and depressive episodes. Thereby, the protective effect of the treatment relates to the extent to which patients increase the regularity of their social rhythms (Frank et al, 2005) and, as shown most recently, this same intervention is associated with recovery from bipolar depression (Miklowitz et al, in press). References [1] Ehlers CL, Frank E, Kupfer DJ, 1988, Social zeitgebers and biological rhythms: A unified approach to understanding the etiology of depression. Arch Gen Psychiatry 45, 948–952. [2] Malkoff-Schwartz S, Frank E, Anderson B, Sherrill JT, Siegel L, Patterson D, Kupfer DJ, 1998, Stressful life events and social rhythm disruption in the onset of manic and depressive bipolar episodes: A Preliminary Investigation. Arch Gen Psychiatry 55(8), 702–707. [3] Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz H, Fagiolini AM, Grochocinski V, Houck P, Scott J, Thompson W, Monk T, 2005, Two year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiatry 62, 996–1004.
C.05.02 Molecular mechanisms of the mammalian circadian clock: identifying the clock genes M. Hastings ° . MRC Laboratory, of Molecular Biology, Cambridge, United Kingdom The suprachiasmatic nuclei (SCN) of the hypothalamus constitute the principal pacemaker coordinating circadian rhythms in the brain and periphery (Hastings et al., 2003). When isolated in vitro, the SCN exhibit circadian cycles of metabolism, electrical firing, and gene expression. In vivo, these intrinsic cycles are entrained to solar time by direct retinal innervation of the SCN. The recent identification of circadian clock genes has revealed a molecular clockwork based upon autoregulatory transcriptional negative feedback loops, pivoted around the circadian expression of the Period and Cryptochrome genes. Using genetically encoded fluorescence and bioluminescence reporters driven by the Period gene (Maywood et al., 2006), it is possible to monitor in real time these feedback loops in organotypical SCN cultures. Moreover, real-time studies have also revealed that major organ systems in the periphery and principal brain regions such as hippocampus and cerebellum contain local circadian clocks, based upon the same molecular mechanisms as the SCN. This pervasive expression of cellular circadian clocks offers a totally new way of thinking about the role of circadian mechanisms in health and disease and provides potential for new therapeutic targets. Moreover, it raises the question of how these multiple molecular clocks are synchronised. Recent transcriptomic studies highlight corticosteroid rhythms as major internal synchronisers. Within the brain, neuropeptidergic signals from the SCN are necessary for appropriate control of rhythmic behaviour and physiology (Prosser et al., 2007). Finally, intracellular signalling via the VPAC2 receptor for vasoactive intestinal polypeptide plays a central role in synchronising the clock neurons of the SCN. References [1] Hastings MH, Reddy AB, Maywood ES, 2003, A clockwork web: Circadian timing in brain and periphery, in health and disease. Nat Rev Neurosci 4, 649–661.
[2] Maywood ES, Reddy AB, Wong GK, O’Neill JS, O’Brien JA, McMahon DG, Harmar AJ, Okamura H, Hastings MH, 2006, Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr Biol 16, 599–605. [3] Prosser HM, Bradley A, Chesham JE, Ebling FJ, Hastings MH, Maywood ES, 2007, Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proc Natl Acad Sci USA 104, 648–653.
C.05.03 Rhythm hypotheses of mood and sleep disorders G. Hajak ° . University of Regensburg, Department of Psychiatry and Psychotherapy, Regensburg, Germany Disruption of main circadian rhythms is a common feature of a wide range of affective disorders, such as depression, mania, and seasonal depression, and may manifest as periodicity of recurrence, diurnal variation of mood, early morning awakening, and sleep-wake cycle disturbances. Numerous variables reflect the presence of circadian abnormalities in patients with major depression, including daily hormone profiles, body temperature, melatonin secretion, as well as sleep timing and structure. These variables may show earlier or delayed timing, diminished amplitude, or greater day-to-day variability. However, whether this altered rhythmicity is a cause or an effect of altered affective states remains a matter of debate. The sleep-wake cycle is the most obvious circadian rhythm in humans, and sleep disturbances have been considered a cardinal symptom of endogenous depression. Sleep disturbances such as insomnia, early awakening, reduced sleep efficiency, and decreased rapid eye movement (REM) sleep latency have been reported both in unipolar and bipolar depression and are well-known to often precede relapses. Antidepressive and hypnotic treatment has been shown to affect circadian functions in man. Available treatments for depression-associated circadian disorders include total and partial sleep deprivation, which is followed by an immediate and short-lasting improvement in depressed mood; the neurohormone melatonin and melatonergic receptors agonists which generally improves sleep in depressed patients through their chronobiotic and homeostatic properties; and, finally, light therapy, which is the treatment of choice for seasonal depression. Recent findings on the methods for increasing zeitgeber strength to achieve entrainment of circadian rhythms are discussed. References [1] Benedetti F, Barbini B, Campori E, Fulgosi MC, Pontiggia A, Colombo C, 2001, Sleep phase advance and lithium to sustain the antidepressant effect of total sleep deprivation in bipolar depression: new findings supporting the internal coincidence model. J Psychiatr Res 35, 323–329. [2] Dolberg OT, Hirschmann S, Grunhaus L, 1998, Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry 155, 1119–1121.
C.05.04 Targeting the melatonergic system: a new approach to treat depression M. Hamon ° . France The biological clock located in the suprachiasmatic nucleus within the hypothalamus plays a central role in the daily programming of organ functions by regulating oscillations of the internal milieu and synchronizing them to the changing day/night cycles. Abnormal patterns of circadian rhythms are associated with a
C.06. Patient monitoring in schizophrenia – improving outcome variety of affective disorders, including major depressive disorder. These circadian abnormalities include the daily profile of various hormones (prolactin, corticotropin-releasing hormone, cortisol, growth hormone, thyroid stimulating hormone, melatonin, etc), body temperature, excretion of various metabolites in the urine, as well as sleep-timing and sleep-structure. The most consistent finding on endogenous melatonin secretion in major depressive dosorder is its lower blood concentration during nighttime and, frequently, the abnormal phasing of the melatonin secretion. The high prevalence of circadian dysfunction in major depressive disorder and the dramatic improvement observed in some depressed patients in response to treatments involving manipulation of their circadian rhythms (and/or of their sleep-wake cycle) suggest that the human circadian system may hold important clues regarding new pharmacological approaches in depression. The efficacy of treatments consisting in circadian manipulation of the sleep-wake cycle in depressed patients suggests that melatonergic agonists might be a helpful therapeutic intervention., even though for melatonin no antidepressant efficacy has been seen. Therapeutic strategies with compounds having, besides melatonergic properties, other receptor affinities (such as pharmacological agents acting at melatonergic and 5-HT2c receptors), could represent new approaches to depression.
C.06. Patient monitoring in schizophrenia – improving outcome C.06.01 What results should we as carers expect from schizophrenia treatment in the 21st century? J. Loughran ° . Rethink, Campaigns and Media, London, United Kingdom In the spring of 2005, Rethink carried out a series of focus groups with service users and carers. The study showed that carers had concerns about feeling valued and respected, and felt that professionals did not recognise the valuable information which they could impart. The lack of supportive feeling contributed to a reluctance for carers to share information with the relevant professional. Service users also felt that meetings were just communication vehicles for decisions that had already been made. There are also a number of common reasons as to why patients are unhappy with the care and treatment they receive from doctors. For many people a visit to the doctor can bring on anxieties and frustrations and, increasingly, there is limited time for appointments with GP’s. This is reflected in the number of people who are given advice and do not follow it, or are prescribed medicines and do not take them as directed. Non-compliance is most often found in poor patient-doctor relationships – in order to change this and for this partnership to work, both parties need to take active roles. The relationship should foster the opportunity for patients to understand their illness and make informed decisions about their treatment and the impact of their diagnosis, and treatment, on physical health. Patients should be ready to talk about their views of their illness and treatment built on informed choice and be prepared to make a joint decision on what treatment they would like and feel would benefit them. References [1] Faulkner A, Williams K, 2005, Future Perfect, mental health service users set out a vision for the 21st century, Rethink.
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C.06.02 Predictors of individual response and long-term compliance in schizophrenia treatment C.A. Tamminga ° . University of Texas, Dept. of Psychiatry, Dallas, USA The response to antipsychotic medication has been shown to be extremely patient specific. In the CATIE study, the majority of patients discontinued antipsychotic medication within the first 18 months of treatment due to lack of efficacy, intolerable side effects, or lack of compliance. Thus, the search for the most appropriate and effective medication for each patient may mean patients require at least one switch of antipsychotic. Identification of the factors that may influence response could potentially reduce the number of switches required. A 12-month, open-label study of 358 patients explored 29 variables for their potential as predictors of treatment response to sertindole in patients with schizophrenia. The study identified six variables that may influence treatment response; patient weight, disease severity, number of courses of electroconvulsive therapy, history of suicide attempts, treatment length before diagnosis, and history of drug abuse. Hazard ratios and likelihood estimates may be used to calculate a ‘prognostic index’ which may be useful when considering a switch to sertindole (Tamminga et al, 2007). This type of information is crucial to the drive to improve response to treatment and patient compliance in schizophrenia. Individualised patient care will facilitate the selection of an antipsychotic medication regimen that the patient is most like to comply with. This selection process should involve working closely with the patient so that they understand their options and the consequences of non-compliance, choosing an antipsychotic with proven efficacy against their dominant symptoms, and ensuring that side effects are minimised in order to encourage their compliance. References [1] Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators, 2005, Effectiveness of antipsychotic drugs in patients with chronic schizophrenia, N Engl J Med 353(12), 1209– 1223. [2] Tamminga C, Tanghoj P, Eberhard J, 2007, Identification of potential predictors of sertindole response in patients with schizophrenia, Poster presented at the 15th European Congress of Psychiatry, March 17−21, Madrid, Spain.
C.06.03 Switch and augmentation strategies in antipsychotic treatment: What can we learn from trials and patient cases? J. Nielsen ° . Aalborg Psychiatric Hospital, Unit for Psychiatric Research, Aalborg, Denmark The majority of patients discontinue antipsychotic medication within the first 18 months of treatment (Lieberman et al, 2005). The search for the most appropriate medication may mean patients require at least one switch. There is only limited evidence on antipsychotic switching strategies, clinical trials and patient cases must be utilised to establish the optimal switching strategy for individuals. In the CATIE study, 24−34% of patients discontinued their medication through their own decision. Cognitive deficits and poor
C.05. From circadian rhythm disorders to psychiatric diseases
developed two lines of evidence in support of this hypothesis. We demonstrated that life events characterized by social rhythm disruption are temporally associated with onset of mood episodes, particularly mania, among individuals with a history of bipolar disorder (Malkoff-Schwartz et al, 1998; 2000). We now have demonstrated that a psychotherapeutic intervention for bipolar disorder specifically targeting the regularizing of daily routines is associated with the prevention of both manic and depressive episodes. Thereby, the protective effect of the treatment relates to the extent to which patients increase the regularity of their social rhythms (Frank et al, 2005) and, as shown most recently, this same intervention is associated with recovery from bipolar depression (Miklowitz et al, in press). References [1] Ehlers CL, Frank E, Kupfer DJ, 1988, Social zeitgebers and biological rhythms: A unified approach to understanding the etiology of depression. Arch Gen Psychiatry 45, 948–952. [2] Malkoff-Schwartz S, Frank E, Anderson B, Sherrill JT, Siegel L, Patterson D, Kupfer DJ, 1998, Stressful life events and social rhythm disruption in the onset of manic and depressive bipolar episodes: A Preliminary Investigation. Arch Gen Psychiatry 55(8), 702–707. [3] Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz H, Fagiolini AM, Grochocinski V, Houck P, Scott J, Thompson W, Monk T, 2005, Two year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiatry 62, 996–1004.
C.05.02 Molecular mechanisms of the mammalian circadian clock: identifying the clock genes M. Hastings ° . MRC Laboratory, of Molecular Biology, Cambridge, United Kingdom The suprachiasmatic nuclei (SCN) of the hypothalamus constitute the principal pacemaker coordinating circadian rhythms in the brain and periphery (Hastings et al., 2003). When isolated in vitro, the SCN exhibit circadian cycles of metabolism, electrical firing, and gene expression. In vivo, these intrinsic cycles are entrained to solar time by direct retinal innervation of the SCN. The recent identification of circadian clock genes has revealed a molecular clockwork based upon autoregulatory transcriptional negative feedback loops, pivoted around the circadian expression of the Period and Cryptochrome genes. Using genetically encoded fluorescence and bioluminescence reporters driven by the Period gene (Maywood et al., 2006), it is possible to monitor in real time these feedback loops in organotypical SCN cultures. Moreover, real-time studies have also revealed that major organ systems in the periphery and principal brain regions such as hippocampus and cerebellum contain local circadian clocks, based upon the same molecular mechanisms as the SCN. This pervasive expression of cellular circadian clocks offers a totally new way of thinking about the role of circadian mechanisms in health and disease and provides potential for new therapeutic targets. Moreover, it raises the question of how these multiple molecular clocks are synchronised. Recent transcriptomic studies highlight corticosteroid rhythms as major internal synchronisers. Within the brain, neuropeptidergic signals from the SCN are necessary for appropriate control of rhythmic behaviour and physiology (Prosser et al., 2007). Finally, intracellular signalling via the VPAC2 receptor for vasoactive intestinal polypeptide plays a central role in synchronising the clock neurons of the SCN. References [1] Hastings MH, Reddy AB, Maywood ES, 2003, A clockwork web: Circadian timing in brain and periphery, in health and disease. Nat Rev Neurosci 4, 649–661.
[2] Maywood ES, Reddy AB, Wong GK, O’Neill JS, O’Brien JA, McMahon DG, Harmar AJ, Okamura H, Hastings MH, 2006, Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr Biol 16, 599–605. [3] Prosser HM, Bradley A, Chesham JE, Ebling FJ, Hastings MH, Maywood ES, 2007, Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proc Natl Acad Sci USA 104, 648–653.
C.05.03 Rhythm hypotheses of mood and sleep disorders G. Hajak ° . University of Regensburg, Department of Psychiatry and Psychotherapy, Regensburg, Germany Disruption of main circadian rhythms is a common feature of a wide range of affective disorders, such as depression, mania, and seasonal depression, and may manifest as periodicity of recurrence, diurnal variation of mood, early morning awakening, and sleep-wake cycle disturbances. Numerous variables reflect the presence of circadian abnormalities in patients with major depression, including daily hormone profiles, body temperature, melatonin secretion, as well as sleep timing and structure. These variables may show earlier or delayed timing, diminished amplitude, or greater day-to-day variability. However, whether this altered rhythmicity is a cause or an effect of altered affective states remains a matter of debate. The sleep-wake cycle is the most obvious circadian rhythm in humans, and sleep disturbances have been considered a cardinal symptom of endogenous depression. Sleep disturbances such as insomnia, early awakening, reduced sleep efficiency, and decreased rapid eye movement (REM) sleep latency have been reported both in unipolar and bipolar depression and are well-known to often precede relapses. Antidepressive and hypnotic treatment has been shown to affect circadian functions in man. Available treatments for depression-associated circadian disorders include total and partial sleep deprivation, which is followed by an immediate and short-lasting improvement in depressed mood; the neurohormone melatonin and melatonergic receptors agonists which generally improves sleep in depressed patients through their chronobiotic and homeostatic properties; and, finally, light therapy, which is the treatment of choice for seasonal depression. Recent findings on the methods for increasing zeitgeber strength to achieve entrainment of circadian rhythms are discussed. References [1] Benedetti F, Barbini B, Campori E, Fulgosi MC, Pontiggia A, Colombo C, 2001, Sleep phase advance and lithium to sustain the antidepressant effect of total sleep deprivation in bipolar depression: new findings supporting the internal coincidence model. J Psychiatr Res 35, 323–329. [2] Dolberg OT, Hirschmann S, Grunhaus L, 1998, Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry 155, 1119–1121.
C.05.04 Targeting the melatonergic system: a new approach to treat depression M. Hamon ° . France The biological clock located in the suprachiasmatic nucleus within the hypothalamus plays a central role in the daily programming of organ functions by regulating oscillations of the internal milieu and synchronizing them to the changing day/night cycles. Abnormal patterns of circadian rhythms are associated with a
C.06. Patient monitoring in schizophrenia – improving outcome variety of affective disorders, including major depressive disorder. These circadian abnormalities include the daily profile of various hormones (prolactin, corticotropin-releasing hormone, cortisol, growth hormone, thyroid stimulating hormone, melatonin, etc), body temperature, excretion of various metabolites in the urine, as well as sleep-timing and sleep-structure. The most consistent finding on endogenous melatonin secretion in major depressive dosorder is its lower blood concentration during nighttime and, frequently, the abnormal phasing of the melatonin secretion. The high prevalence of circadian dysfunction in major depressive disorder and the dramatic improvement observed in some depressed patients in response to treatments involving manipulation of their circadian rhythms (and/or of their sleep-wake cycle) suggest that the human circadian system may hold important clues regarding new pharmacological approaches in depression. The efficacy of treatments consisting in circadian manipulation of the sleep-wake cycle in depressed patients suggests that melatonergic agonists might be a helpful therapeutic intervention., even though for melatonin no antidepressant efficacy has been seen. Therapeutic strategies with compounds having, besides melatonergic properties, other receptor affinities (such as pharmacological agents acting at melatonergic and 5-HT2c receptors), could represent new approaches to depression.
C.06. Patient monitoring in schizophrenia – improving outcome C.06.01 What results should we as carers expect from schizophrenia treatment in the 21st century? J. Loughran ° . Rethink, Campaigns and Media, London, United Kingdom In the spring of 2005, Rethink carried out a series of focus groups with service users and carers. The study showed that carers had concerns about feeling valued and respected, and felt that professionals did not recognise the valuable information which they could impart. The lack of supportive feeling contributed to a reluctance for carers to share information with the relevant professional. Service users also felt that meetings were just communication vehicles for decisions that had already been made. There are also a number of common reasons as to why patients are unhappy with the care and treatment they receive from doctors. For many people a visit to the doctor can bring on anxieties and frustrations and, increasingly, there is limited time for appointments with GP’s. This is reflected in the number of people who are given advice and do not follow it, or are prescribed medicines and do not take them as directed. Non-compliance is most often found in poor patient-doctor relationships – in order to change this and for this partnership to work, both parties need to take active roles. The relationship should foster the opportunity for patients to understand their illness and make informed decisions about their treatment and the impact of their diagnosis, and treatment, on physical health. Patients should be ready to talk about their views of their illness and treatment built on informed choice and be prepared to make a joint decision on what treatment they would like and feel would benefit them. References [1] Faulkner A, Williams K, 2005, Future Perfect, mental health service users set out a vision for the 21st century, Rethink.
S601
C.06.02 Predictors of individual response and long-term compliance in schizophrenia treatment C.A. Tamminga ° . University of Texas, Dept. of Psychiatry, Dallas, USA The response to antipsychotic medication has been shown to be extremely patient specific. In the CATIE study, the majority of patients discontinued antipsychotic medication within the first 18 months of treatment due to lack of efficacy, intolerable side effects, or lack of compliance. Thus, the search for the most appropriate and effective medication for each patient may mean patients require at least one switch of antipsychotic. Identification of the factors that may influence response could potentially reduce the number of switches required. A 12-month, open-label study of 358 patients explored 29 variables for their potential as predictors of treatment response to sertindole in patients with schizophrenia. The study identified six variables that may influence treatment response; patient weight, disease severity, number of courses of electroconvulsive therapy, history of suicide attempts, treatment length before diagnosis, and history of drug abuse. Hazard ratios and likelihood estimates may be used to calculate a ‘prognostic index’ which may be useful when considering a switch to sertindole (Tamminga et al, 2007). This type of information is crucial to the drive to improve response to treatment and patient compliance in schizophrenia. Individualised patient care will facilitate the selection of an antipsychotic medication regimen that the patient is most like to comply with. This selection process should involve working closely with the patient so that they understand their options and the consequences of non-compliance, choosing an antipsychotic with proven efficacy against their dominant symptoms, and ensuring that side effects are minimised in order to encourage their compliance. References [1] Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators, 2005, Effectiveness of antipsychotic drugs in patients with chronic schizophrenia, N Engl J Med 353(12), 1209– 1223. [2] Tamminga C, Tanghoj P, Eberhard J, 2007, Identification of potential predictors of sertindole response in patients with schizophrenia, Poster presented at the 15th European Congress of Psychiatry, March 17−21, Madrid, Spain.
C.06.03 Switch and augmentation strategies in antipsychotic treatment: What can we learn from trials and patient cases? J. Nielsen ° . Aalborg Psychiatric Hospital, Unit for Psychiatric Research, Aalborg, Denmark The majority of patients discontinue antipsychotic medication within the first 18 months of treatment (Lieberman et al, 2005). The search for the most appropriate medication may mean patients require at least one switch. There is only limited evidence on antipsychotic switching strategies, clinical trials and patient cases must be utilised to establish the optimal switching strategy for individuals. In the CATIE study, 24−34% of patients discontinued their medication through their own decision. Cognitive deficits and poor