- Email: [email protected]
P.2.b.036 The outcome of major depressive disorder comorbid diabetes
P.2.b. Mood disorders and treatment − Affective disorders (clinical) all patients. Therefore, the European Medicines Agency requires the monitoring of liver function tests during the first 24 weeks of initiation and then as clinically indicated, and is contraindicated in patients with impaired liver function [1,4]. Objectives: The aim of this study was to examine the liver function safety of agomelatine in the treatment of patients with major depressive disorder. Methods: Depressed outpatients (N = 70) who were receiving antidepressant treatment with agomelatine (25−50 mg/) were included during 2014 in this observational open study. 7 patients were withdrawn because they discontinued the treatment study before the first liver function test. Participants met DSM-IVTR criteria for major depressive episode [5]. Liver function test, including aspartate aminotransferase (AST), alanine aminotransferase ((ALT) and gamma-glutamyl transferase (GGT), were at limit of normal level in all cases at baseline and were performed after treatment at weeks 3, 6, 12 and 24, during a follow-up period. The criterion for clinically notable values for transaminases in the blood is more than three times the upper limit of normal level (ULN: AST 1−35 U/L; ALT 2−40 U/L; GGT 11−50 U/L). Results: 63 patients (28 males and 35 females; mean age: 50,89 (22−80); 11 patients more than 65 aged) performed the liver function tests. 40 of them completed the four tests and 23 are still during the follow-up period. None of the clinically notable liver enzyme elevations in the blood were reported. In general, the aminotransferase elevations occurred mainly between weeks 3 and 6 of the treatment and were transient. They were principally observed with agomelatine at a dose of 50 mg per day. Overall, 12 patients (19%) experienced mild elevations in ALT/AST/GGT and the enzyme values decreased to normal levels with continuing agomelatine treatment. The maximum value of aminotransferase elevation was more than two times the upper limit of normal level (GGT 101 U/L at third week) and that occurred in only 1 case (male 46-aged). None of the observed elevations were associated with any sign of liver toxicity (nor clinical symptomatology). None of the liver enzymes elevations in the blood were found on elder patients (N = 6 aged between 75−80). Conclusions: Regardless of these limitations, these study findings confirm the safety of agomelatine by monitoring of liver function tests during the first 24 weeks of initiation treatment, in both young and elder. The small N and the methods used in this study do not generalize the results, although they represent a clinical finding that should be verified in further studies to establish the evidence. References [1] EMEA, 2009. Agomelatine: summary of product characteristics. (Product information http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_Product_Information/human/000915/ WC500046227.pdf). [2] Stahl, S.M., Fava, M. et al, 2010. Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebocontrolled trial. Journal of Clinical Psychiatry 71(5), 616–626. [3] Hale, A., Corral, R.M., Mencacci, C. et al, 2010. Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized, double-blind study. International Clinical Psychopharmacology 25, 305–314. [4] Green B., 2011. Focus on agomelatine. Current Medical Research and Opinion 27, 745–749. s fluoxetine in severe MDD patients: a randomized, double-blind study. International Clinical Psychopharmacology 25, 305–314. [5] APA, 2000. DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Press Inc. mized, double-blind study. International Clinical Psychopharmacology 25, 305–314. Disclosure statement: 28 ECNP registration fees, Lab. Servier
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P.2.b.036 The outcome of major depressive disorder comorbid diabetes P. Ju1 ° , H. Ming-Hong2 , C. Jeng-Yuan3 , W. Yu-Hsun4 1 Chung Shan Medical University Hospital, Psychiatry, Taichung City, Taiwan; 2 Chung Shan Medical University Hospital, Psychiatry, Taiching City, Taiwan; 3 Chung Shan Medical University, School of Health Policy and Management, Taichung City, Taiwan; 4 Chung Shan Medical University Hospital, Medical Research, Taichung City, Taiwan Major depression not only affects brain and behavior—it affects entire body. Major depression has been linked with other health problems, including diabetes. Some studies show that depression and diabetes may be linked, but clinicians do not yet know whether depression increases the risk of diabetes or diabetes increases the risk of depression. In addition to possibly increasing your risk for depression, diabetes may make symptoms of depression worse. For example, overeating may cause body weight gain, a major risk factor for diabetes. Psychomotor retardation or feelings of hopelessness may cause you to ignore a special diet or medication plan needed to control your diabetes, worsening your diabetes symptoms. Some studies have shown that people with diabetes and depression have more severe diabetes symptoms than people who have diabetes alone. We aimed at evaluation the outcome in a diabetes shared care program among patients with major depressive disorder comorbid diabetes. The dataset used in this study were compiled from the Psychiatric Inpatients Medical Claims Data (PIMC) released by the National Health Research Institute (NHRI) in Taiwan. Patients with major depressive disorder diagnosed between 1999 and 2001 with a primary International Classification of Diseases, Ninth Revision, Clinical Modification code of 296.3 and 296.3 were identified from Psychiatric Medical Claims Data released by the National Health Research Institute in Taiwan. Longitudinal claims data covering the period from January 1, 1999 to December 31, 2005 were collected for patients with major depressive disorder within a specified time frame. Major depressive disorder patients with or without diabetes were included as study subjects. The main outcome variable assessed in this study was the probability of a psychiatric rehospitalization or emergency service use (with principal ICD-9-CM codes of 290– 319) within a 36-month window of observation. The final sample for the study included 630 participants in the diabetes group and 2844 in the non-diabetes group. The cox proportional hazards regression model was performed to examine the independent effect of diabetes group on the risk for rehospitalization and emergency service use within the 36-month observation window after controlling for patient and hospital characteristics and propensity score quintile adjustment. All analyses were performed using the SAS/Stat system for Windows, version 9.01 (SAS Institute, Cary, NC, USA). The odds ratio for the risk of rehospitalization and emergency service use was1.4 (confidence interval, 0.72–2.01) for the diabetes group compared to the non-diabetes group. The odds ratio was further increased to 1.49 (confidence interval,1.04– 2.15) in the diabetes group without the diabetes shared care service. In the diabetes shared care setting, patients with major depressive disorder comorbid diabetes are at a significantly lower risk for psychiatric rehospitalization and emergency service use than those without the diabetes shared care service. Consequently, the diabetes shared care program for the prevention of major depressive disorder relapse may lead to substantial clinical and economic benefits in patients comorbid diabetes.
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P.2.c. Mood disorders and treatment − Bipolar disorders (basic)
References [1] Egede, L.E., Zheng, D., Simpson, K. Comorbid depression is associated with increased health care use and expenditures in individuals with diabetes. Diabetes Care. 2002 Mar; 25(3):464−70. [2] Golden, S.H., Lazo, M., Carnethon, M., Bertoni, A,G., Schreiner, P.J., Roux, A.V., Lee, H.B., Lyketsos, C. Examining a bidirectional association between depressive symptoms and diabetes. JAMA. 2008 Jun 18; 299(23):2751−9. [3] Kumar, A., Gupta, R., Thomas, A., Ajilore, O., Hellemann, G. Focal subcortical biophysical abnormalities in patients diagnosed with type 2 diabetes and depression. Arch Gen Psychiatry. 2009 Mar; 66(3):324−30. [4] Hao, L.J., Tien, K.J., Chao, H., 2011. Metabolic outcome for diabetes shared program outpatients in a veterans hospital of southern Taiwan. Journal of the Chinese Medical Association, 287–293.
P.2.c. Mood disorders and treatment − Bipolar disorders (basic) P.2.c.001 Determining the CNS effects of ebselen: a potential lithium-mimetic N. Singh1 ° , A. Sharpley1 , U. Emir2 , C. Masaki1 , T. Sharp3 , C. Harmer1 , S. Vasudevan3 , P. Cowen1 , G. Churchill3 1 University of Oxford, Department of Psychiatry, Oxford, United Kingdom; 2 University of Oxford, Nuffield Department of Clinical Neurosciences, Oxford, United Kingdom; 3 University of Oxford, Department of Pharmacology, Oxford, United Kingdom Background: Bipolar disorder has a lifetime prevalence of 3.9% (1) and is a life-long, debilitating mental health illness. Lithium is the gold standard for the treatment of bipolar disorder and although efficacious, it has problematic side effects, and a narrow therapeutic index. Therefore, it remains crucial to develop new lithium-like drugs. One of lithium’s possible therapeutic targets is inositol monophosphatase (IMPase), and recently, it was reported that ebselen, a drug originally developed for it’s antioxidant and anti-inflammatory properties, was a potent IMPase inhibitor (2). In animal models, ebselen has some lithium-like effects, and since it has a known clinical safety, it can be studied in man. Objective: To demonstrate that ebselen, a potential lithiummimetic, (a) shows target engagement in the brain by virtue of lowering myo-inositol, which is a product of IMPase; and (b) to characterise the central nervous system (CNS) effects of ebselen in an experimental medicine study with healthy volunteers. Methods: In a randomised, double-blind, placebo controlled, cross-over healthy volunteer (n = 16) study, we assessed the effects of ebselen on brain myo-inositol levels using proton magnetic resonance spectroscopy following 3 × 600 mg doses of ebselen, and in the same cohort, the effect the on sleep architecture after 4 × 600 mg doses. In a separate double-blind, placebo controlled, randomised, parallel group healthy volunteer (n = 40) study, we administered 3 × 600 mg ebselen and tested the effects on tasks of emotional processing. Questionnaires were also used to determine baseline characteristics of the groups, quality of sleep and sideeffects, if any. Statistical significance was ascertained by t-tests, curve fitting, or repeated measures ANOVA, as appropriate. Results: myo-Inositol: Ebselen decreased myo-inositol in the anterior cingulate cortex compared to placebo (p = 0.026), but not in the occipital cortex. Sleep: In the sleep polysomnogram, ebselen decreased slowwave sleep significantly (p = 0.035). It had no effect on any other
sleep parameters, for example, Rapid Eye Movement (REM). Additionally, ebselen did not affect the quality of sleep as measured by the Leeds Sleep Evaluation Questionnaire. Emotional processing: In the facial expression recognition task, participants on ebselen showed an increase in recognition of ‘disgust’ and ‘happiness’ (p < 0.0001 and p = 0.003, respectively). In a reward-punishment task, ebselen showed a decrease in the learning of reward reinforcement stimuli, and a trend in increased learning of punishment (p = 0.01). Finally, ebselen showed a decreased latency to response in an acoustic startle task (p = 0.01). Ebselen had no effect on positive or negative emotional memory tasks, the attentional vigilance task, and the auditory verbal learning task (AVLT). There were no statistically significant differences between the ebselen and placebo groups, with regard to demographics and baseline questionnaire measures. Conclusion: Ebselen lowered myo-inositol and hence showed that it inhibits IMPase in vivo. Additionally, ebselen showed CNS effects in various tasks designed to demonstrate effects of psychoactive drugs. Ebselen was found to be safe and well tolerated at the doses administered. Hence, a clinical trial for testing the efficacy of ebselen in bipolar disorder is warranted. References [1] Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE (2005): Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62: 593–602. [2] Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon ECY, et al. (2013): A safe lithium mimetic for bipolar disorder. Nat Comms 4: 1332.
P.2.c.002 Gene expression profile of DGKH risk variant carriers with bipolar disorder S. Kittel-Schneider1 ° , C. Lorenz2 , J. Auer1 , A. Reif1 1 University of Frankfurt, Department of Psychiatry − Psychosomatics and Psychotherapy, Frankfurt am Main, Germany; 2 University of W¨urzburg, Department of Psychiatry, W¨urzburg, Germany Purpose of the study: Bipolar disorder (BD) has a high heritability and several risk gene variants have emerged throughout the last years in genome wide association studies. DGKH is one of the best replicated risk genes [1]. Own previous work could show a DGKH haplotype (rs994856/rs9525580/rs9525584 GAT) being associated with BD [2] and also having an influence on amygdala volume specifically in BD patients [3]. However, the pathophysiological role of the coded protein, diacylglyerol kinase eta, remains elusive, studies to functionally characterize the risk gene variant are rare. Methods: In this proof-of-concept study we isolated RNA from peripheral blood and fibroblasts of 10 DGKH risk variants carriers (heterozygote) with bipolar disorder and 9 non-risk variant carriers with and without bipolar disorder. Healthy risk variant carriers could not be included in this study due to the significant less frequency of the GAT risk haplotyope in healthy population. The majority of BD patients were taking mood stabilizing patients and patients in a acute depressed, as well as in a acute manic state as also euthymic patients were recruited. The sample was sex- and age-matched. Gene expression of DGKH1, DGKH2, INPP5E, PI4K2B, PIK4CA, PLCG2, PRKCA, PRKCD, PRKCE and PRKCH was analyzed by quantitative Real Time PCR. Candidate genes were chosen from the multiple interacting proteins
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P.2.b.036 The outcome of major depressive disorder comorbid diabetes P. Ju1 ° , H. Ming-Hong2 , C. Jeng-Yuan3 , W. Yu-Hsun4 1 Chung Shan Medical University Hospital, Psychiatry, Taichung City, Taiwan; 2 Chung Shan Medical University Hospital, Psychiatry, Taiching City, Taiwan; 3 Chung Shan Medical University, School of Health Policy and Management, Taichung City, Taiwan; 4 Chung Shan Medical University Hospital, Medical Research, Taichung City, Taiwan Major depression not only affects brain and behavior—it affects entire body. Major depression has been linked with other health problems, including diabetes. Some studies show that depression and diabetes may be linked, but clinicians do not yet know whether depression increases the risk of diabetes or diabetes increases the risk of depression. In addition to possibly increasing your risk for depression, diabetes may make symptoms of depression worse. For example, overeating may cause body weight gain, a major risk factor for diabetes. Psychomotor retardation or feelings of hopelessness may cause you to ignore a special diet or medication plan needed to control your diabetes, worsening your diabetes symptoms. Some studies have shown that people with diabetes and depression have more severe diabetes symptoms than people who have diabetes alone. We aimed at evaluation the outcome in a diabetes shared care program among patients with major depressive disorder comorbid diabetes. The dataset used in this study were compiled from the Psychiatric Inpatients Medical Claims Data (PIMC) released by the National Health Research Institute (NHRI) in Taiwan. Patients with major depressive disorder diagnosed between 1999 and 2001 with a primary International Classification of Diseases, Ninth Revision, Clinical Modification code of 296.3 and 296.3 were identified from Psychiatric Medical Claims Data released by the National Health Research Institute in Taiwan. Longitudinal claims data covering the period from January 1, 1999 to December 31, 2005 were collected for patients with major depressive disorder within a specified time frame. Major depressive disorder patients with or without diabetes were included as study subjects. The main outcome variable assessed in this study was the probability of a psychiatric rehospitalization or emergency service use (with principal ICD-9-CM codes of 290– 319) within a 36-month window of observation. The final sample for the study included 630 participants in the diabetes group and 2844 in the non-diabetes group. The cox proportional hazards regression model was performed to examine the independent effect of diabetes group on the risk for rehospitalization and emergency service use within the 36-month observation window after controlling for patient and hospital characteristics and propensity score quintile adjustment. All analyses were performed using the SAS/Stat system for Windows, version 9.01 (SAS Institute, Cary, NC, USA). The odds ratio for the risk of rehospitalization and emergency service use was1.4 (confidence interval, 0.72–2.01) for the diabetes group compared to the non-diabetes group. The odds ratio was further increased to 1.49 (confidence interval,1.04– 2.15) in the diabetes group without the diabetes shared care service. In the diabetes shared care setting, patients with major depressive disorder comorbid diabetes are at a significantly lower risk for psychiatric rehospitalization and emergency service use than those without the diabetes shared care service. Consequently, the diabetes shared care program for the prevention of major depressive disorder relapse may lead to substantial clinical and economic benefits in patients comorbid diabetes.
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P.2.c. Mood disorders and treatment − Bipolar disorders (basic)
References [1] Egede, L.E., Zheng, D., Simpson, K. Comorbid depression is associated with increased health care use and expenditures in individuals with diabetes. Diabetes Care. 2002 Mar; 25(3):464−70. [2] Golden, S.H., Lazo, M., Carnethon, M., Bertoni, A,G., Schreiner, P.J., Roux, A.V., Lee, H.B., Lyketsos, C. Examining a bidirectional association between depressive symptoms and diabetes. JAMA. 2008 Jun 18; 299(23):2751−9. [3] Kumar, A., Gupta, R., Thomas, A., Ajilore, O., Hellemann, G. Focal subcortical biophysical abnormalities in patients diagnosed with type 2 diabetes and depression. Arch Gen Psychiatry. 2009 Mar; 66(3):324−30. [4] Hao, L.J., Tien, K.J., Chao, H., 2011. Metabolic outcome for diabetes shared program outpatients in a veterans hospital of southern Taiwan. Journal of the Chinese Medical Association, 287–293.
P.2.c. Mood disorders and treatment − Bipolar disorders (basic) P.2.c.001 Determining the CNS effects of ebselen: a potential lithium-mimetic N. Singh1 ° , A. Sharpley1 , U. Emir2 , C. Masaki1 , T. Sharp3 , C. Harmer1 , S. Vasudevan3 , P. Cowen1 , G. Churchill3 1 University of Oxford, Department of Psychiatry, Oxford, United Kingdom; 2 University of Oxford, Nuffield Department of Clinical Neurosciences, Oxford, United Kingdom; 3 University of Oxford, Department of Pharmacology, Oxford, United Kingdom Background: Bipolar disorder has a lifetime prevalence of 3.9% (1) and is a life-long, debilitating mental health illness. Lithium is the gold standard for the treatment of bipolar disorder and although efficacious, it has problematic side effects, and a narrow therapeutic index. Therefore, it remains crucial to develop new lithium-like drugs. One of lithium’s possible therapeutic targets is inositol monophosphatase (IMPase), and recently, it was reported that ebselen, a drug originally developed for it’s antioxidant and anti-inflammatory properties, was a potent IMPase inhibitor (2). In animal models, ebselen has some lithium-like effects, and since it has a known clinical safety, it can be studied in man. Objective: To demonstrate that ebselen, a potential lithiummimetic, (a) shows target engagement in the brain by virtue of lowering myo-inositol, which is a product of IMPase; and (b) to characterise the central nervous system (CNS) effects of ebselen in an experimental medicine study with healthy volunteers. Methods: In a randomised, double-blind, placebo controlled, cross-over healthy volunteer (n = 16) study, we assessed the effects of ebselen on brain myo-inositol levels using proton magnetic resonance spectroscopy following 3 × 600 mg doses of ebselen, and in the same cohort, the effect the on sleep architecture after 4 × 600 mg doses. In a separate double-blind, placebo controlled, randomised, parallel group healthy volunteer (n = 40) study, we administered 3 × 600 mg ebselen and tested the effects on tasks of emotional processing. Questionnaires were also used to determine baseline characteristics of the groups, quality of sleep and sideeffects, if any. Statistical significance was ascertained by t-tests, curve fitting, or repeated measures ANOVA, as appropriate. Results: myo-Inositol: Ebselen decreased myo-inositol in the anterior cingulate cortex compared to placebo (p = 0.026), but not in the occipital cortex. Sleep: In the sleep polysomnogram, ebselen decreased slowwave sleep significantly (p = 0.035). It had no effect on any other
sleep parameters, for example, Rapid Eye Movement (REM). Additionally, ebselen did not affect the quality of sleep as measured by the Leeds Sleep Evaluation Questionnaire. Emotional processing: In the facial expression recognition task, participants on ebselen showed an increase in recognition of ‘disgust’ and ‘happiness’ (p < 0.0001 and p = 0.003, respectively). In a reward-punishment task, ebselen showed a decrease in the learning of reward reinforcement stimuli, and a trend in increased learning of punishment (p = 0.01). Finally, ebselen showed a decreased latency to response in an acoustic startle task (p = 0.01). Ebselen had no effect on positive or negative emotional memory tasks, the attentional vigilance task, and the auditory verbal learning task (AVLT). There were no statistically significant differences between the ebselen and placebo groups, with regard to demographics and baseline questionnaire measures. Conclusion: Ebselen lowered myo-inositol and hence showed that it inhibits IMPase in vivo. Additionally, ebselen showed CNS effects in various tasks designed to demonstrate effects of psychoactive drugs. Ebselen was found to be safe and well tolerated at the doses administered. Hence, a clinical trial for testing the efficacy of ebselen in bipolar disorder is warranted. References [1] Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE (2005): Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62: 593–602. [2] Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon ECY, et al. (2013): A safe lithium mimetic for bipolar disorder. Nat Comms 4: 1332.
P.2.c.002 Gene expression profile of DGKH risk variant carriers with bipolar disorder S. Kittel-Schneider1 ° , C. Lorenz2 , J. Auer1 , A. Reif1 1 University of Frankfurt, Department of Psychiatry − Psychosomatics and Psychotherapy, Frankfurt am Main, Germany; 2 University of W¨urzburg, Department of Psychiatry, W¨urzburg, Germany Purpose of the study: Bipolar disorder (BD) has a high heritability and several risk gene variants have emerged throughout the last years in genome wide association studies. DGKH is one of the best replicated risk genes [1]. Own previous work could show a DGKH haplotype (rs994856/rs9525580/rs9525584 GAT) being associated with BD [2] and also having an influence on amygdala volume specifically in BD patients [3]. However, the pathophysiological role of the coded protein, diacylglyerol kinase eta, remains elusive, studies to functionally characterize the risk gene variant are rare. Methods: In this proof-of-concept study we isolated RNA from peripheral blood and fibroblasts of 10 DGKH risk variants carriers (heterozygote) with bipolar disorder and 9 non-risk variant carriers with and without bipolar disorder. Healthy risk variant carriers could not be included in this study due to the significant less frequency of the GAT risk haplotyope in healthy population. The majority of BD patients were taking mood stabilizing patients and patients in a acute depressed, as well as in a acute manic state as also euthymic patients were recruited. The sample was sex- and age-matched. Gene expression of DGKH1, DGKH2, INPP5E, PI4K2B, PIK4CA, PLCG2, PRKCA, PRKCD, PRKCE and PRKCH was analyzed by quantitative Real Time PCR. Candidate genes were chosen from the multiple interacting proteins