- Email: [email protected]
C.13.01 The effect of antipsychotic medication on brain structure in schizophrenia
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C.13. The past, present and future treatment of patients with schizophrenia − how far have we come?
[2] Moos, R.H., Moos, B.S., 2006 Rates and predictors of relapse after natural and treated remission from alcohol use disorders. Addiction 101, 212–222. [3] Gastfriend, D.R., et al., 2007 Reduction in heavy drinking as a treatment outcome in alcohol dependence. Journal of Substance Abuse Treatment 33, 71−80. Disclosure statement: Grants: Neurotech Honoraria: Eli Lilly, Lundbeck, Schering-Plough, Pfizer, Merck Serono Advisory boards: Merck Serono, Lundbeck, Schering-Plough, Teva
C.12.02 Engaging patients in the treatment of alcohol dependence − The role of reduction of alcohol consumption and “as-needed” dosing A. Gual1 ° 1 Hospital Clinic, Addictions unit, Barcelona, Spain Traditional methods for treating alcohol dependence have focused on total abstinence. However, many individuals with alcohol dependence are not able, or inclined, to achieve abstinence, resulting in a medical condition that is under-diagnosed and under-treated. In Europe, a small proportion (8.3%) of people diagnosed with alcohol dependence receive treatment [1]. Increasingly, there is an acceptance of reduction of alcohol consumption as part of a continuum of treatment goals for patients with alcohol dependence. Many national and international guidelines endorse reduction as a treatment paradigm. The option of reduction of alcohol consumption lowers the treatment barrier [2] and may help to close the treatment gap. Furthermore, patients may do better when enabled to choose, as opposed to being assigned, a treatment goal. Moreover, allowing patients to have a say in dosing regimens can be considered as a means to engaging patients in active and responsible management of their treatment, improving thereby patient adherence and compliance to treatment. These two aspects were incorporated in the recently completed Phase III program designed to assess the efficacy and safety of nalmefene. The experience with the approximately 2,000 patients enrolled in the studies contributes to prove the feasibility of reduction as an achievable treatment goal and “as needed” dosing in patients with alcohol dependence. In line with the recent changes in modern management of addictions, with patient centred approaches based on internal rather than external confrontation, negotiating treatment goals and dosing regimens are proposed as two valid options towards patient empowerment and therapeutic relationship facilitation. References [1] Alonso, J., et al., 2004 Use of mental health services in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl 420, 47−54. [2] Marlatt, G.A., Witkiewitz, K., 2002 Harm reduction approaches to alcohol use: Health promotion, prevention, and treatment. Addict Behav 27, 867–886. [3] Soyka, M., Rosner, S., 2010 Nalmefene for treatment of alcohol dependence. Expert Opin Investig Drugs 19 (11), 1451–1459. Disclosure statement: Grants: Lundbeck, FP7, SANCO Honoraria: Servier, Lundbeck Advisory boards: Lundbeck.
C.12.03 A potential new treatment for alcohol dependence: results from nalmefene phase III clinical program K. Mann1 ° 1 Central Institute of Mental Health Mannheim University of Heidelberg, Department for Addictive Behaviour, Mannheim, Germany Three multi-centre, double-blind, placebo-controlled Phase III studies, designed to assess the efficacy and safety of nalmefene
in reducing alcohol consumption, enrolled close to 2000 patients with alcohol dependence. Despite a long period (>10 years) of problem drinking, the vast majority of the alcohol-dependent patients included in the nalmefene clinical trials had not previously received any treatment for their condition, underlining the need for a new approach to treating these patients. In the two efficacy studies (ESENSE 1 and ESENSE 2), nalmefene was superior to placebo in reducing the number of heavy drinking days (HDDs, p < 0.05 in both studies) and total alcohol consumption (TAC, ESENSE 1, p < 0.05; ESENSE 2, p = 0.088) at Month 6. In the 1-year safety study (SENSE), nalmefene was superior to placebo (p < 0.05) in reducing the number of HDDs and TAC at the majority of the time points and at the end of the study, although not at Month 6. In all the studies, the effect of nalmefene was evident already at month one and was maintained throughout the treatment period. For all three studies, improvements in CGI scores and reductions in liver enzymes gamma-glutamyltransferase and alanine aminotransferase from baseline were larger in the nalmefene group compared to placebo throughout the study periods. The most frequent adverse events reported included dizziness, insomnia and nausea, and were mild and transient. The majority of these events had an onset within the first days after the first dose and decreased with treatment continuation. Disclosure statement: Grants: Alkermes, Lundbeck, McNeil, MundiPharma, Merck Sharp & Dohme Honoraria: Pfizer, Lundbeck, Alkermes & Desitin Advisory board/consultant: Pfizer, Lundbeck, Alkermes.
C.13. The past, present and future treatment of patients with schizophrenia − how far have we come? C.13.01 The effect of antipsychotic medication on brain structure in schizophrenia S. Frangou1 ° 1 Institute of Psychiatry King’s College London, Section of Neurobiology of Psychosis Department of Psychosis Studies, London, United Kingdom Antipsychotic medication represents the main therapeutic intervention for schizophrenia. The benefits of antipsychotic treatment in symptomatic control are well established. In contrast, evidence regarding their impact on brain structure is still accumulating. Neuroimaging studies have identified widespread brain anatomical changes in patients with schizophrenia. However, since the majority of patients participating in these studies were receiving treatment with antipsychotics, questions have arisen about the contribution of antipsychotic medication to the observed changes. We conducted a narrative review of gray matter structural changes associated with antipsychotic treatment, particularly the use of second generation antipsychotics (SGAs), and a quantitative voxel-based and region of interest meta-analysis of diffusion tensor imaging (DTI) studies (n = 40) in order to elucidate the effect of medication on white matter architecture. SGAs are associated with increased thalamic volume [1] while their effect on cortical gray matter is less clear; some studies suggest a preservative effect of SGAs on gray matter [2], while others do not [3]. Our quantitative meta-analysis of DTI studies in patients with schizophrenia found evidence for SGA treatment being associated
C.13. The past, present and future treatment of patients with schizophrenia − how far have we come? with normalization of DTI measures in the internal capsule, corpus callosum and the white matter of the right cingulate and superior temporal gyri. These results suggest that SGAs may normalize gray and white matter changes in patients with schizophrenia, although the corresponding microstructural changes responsible are unclear. The lack of longitudinal, within-subject designs is a major gap in the current literature. References [1] Tomelleri, L., Jogia, J., Perlini, C., et al. 2009 Brain structural changes associated with chronicity and antipsychotic treatment in schizophrenia. Eur Neuropsychopharmacol 19: 835–840. [2] Lieberman, J.A., Tollefson, G.D., Charles, C., et al. 2005 Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 62: 361–370. [3] Bora, E., Fornito, A., Radua, J., et al. 2011 Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis. Schizophr Res 127: 46−57. Disclosure statement: Sophia Frangou has served as consultant, advisor or speaker for Janssen-Cilag, Bristol-Myers-Squibb/Otsuka and Lundbeck.
C.13.02 Pharmacological and non-pharmacological therapies as integral parts for optimizing patient outcomes A. Schreiner1 ° 1 Janssen EMEA, Department of Medical and Scientific Affairs, Neuss, Germany The care of patients with schizophrenia has shifted from an institutionalized-based approach to one more centered in the community [1]. This approach includes social support and outreach schemes, often conducted by nurses and involving patients’ friends and families. In spite of this change many patients’ first experience of antipsychotic treatment still occurs in hospital. The issues faced in this setting and the treatment options available not only pose many questions for healthcare professionals, but impact on the success of subsequent community-based care. Indeed, balancing non-pharmacological treatments that support social rehabilitation with the need for continuous antipsychotic medication is vital to the management of integrated care in schizophrenia, and to ensuring successful transition from the inpatient to outpatient setting. As well as symptomatic control, treatment goals in the hospital setting frequently include addressing agitation and aggression. While intramuscular depot antipsychotics have been used, their associated side effects can contribute to a negative attitude towards injectable formulations leading many patients to discontinue treatment [2]. Nevertheless, it may be pertinent to consider a possible role for long-acting injectable (LAI) antipsychotics in this setting. Amongst the LAI antipsychotics available, paliperidone palmitate has been shown to offer a rapid onset of efficacy, with reduced risk of relapse compared with placebo in clinical trials, both of which are achieved with acceptable tolerability [3]. As such, LAI antipsychotics may have a role in the hospital setting with the potential for continuous treatment and optimum longer-term patient benefits. References [1] Kirkby, K.C., 2005 Social context and health consequences of the antipsychotics introduction. Ann Clin Psychiatry 17: 141–146. [2] Kasper, S., 2005 Treatment challenges in the acute hospital setting. World J Biol Psychiatry 6: 210–211. [3] Citrome, L., 2010 Paliperidone palmitate − review of the efficacy, safety and cost of a new second-generation depot antipsychotic medication. Int J Clin Pract 64: 216–239. Disclosure statement: Andreas Schreiner is a full-time employee of Janssen.
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C.13.03 Translating the evidence on the clinical benefits of antipsychotics for routine practice S. Leucht1 ° 1 Technische Universit¨at M¨unchen, Department of Psychiatry and Psychotherapy, Munich, Germany Advances in pharmacotherapy have given psychiatrists an increased number of options when selecting the most appropriate treatment for their patients with schizophrenia. Choosing between a number of antipsychotic medications that differ in their receptor binding profiles, formulation and pharmacokinetics is only a part of this selection process. Judging drugs’ effectiveness on the basis of data derived from different outcome parameters, including clinical efficacy, tolerability and patient functioning, whether from randomized controlled trials or naturalistic or observational studies may not be straightforward. In light of these factors, and the scarcity of active comparator trials, meta-analyses of both clinical trial and real-world study data can be instrumental in elucidating the clinical benefits of antipsychotic drugs, and help inform psychiatrists in their daily treatment decision-making. Evidence from meta-analyses has revealed that, compared with placebo, antipsychotics are highly efficacious in preventing relapse [1], both overall and in important subgroups such as first episode patients and stabilized patients. However, there is little long-term data addressing whether second-generation and firstgeneration antipsychotics differ in relapse prevention [2]. Data from large observational and mirror-image studies has helped to show injectable formulations to have superiority over oral formulations in preventing relapse. However, methodological issues (such as the exclusion of non-adherent patients) in some randomizedcontrolled trials may have reduced a potential superiority of depot antipsychotics [3]. By using evidence from large-scale meta-analyses, the impact of various antipsychotic treatment options on clinical practice and their day-to-day relevance for practicing psychiatrists can be better understood. References [1] Leucht, S. et al., 2009 How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 14: 429–447. [2] Leucht, S. et al., 2009 Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373: 31−41. [3] Leucht, C. et al., 2011 Oral versus depot antipsychotic drugs for schizophrenia − a critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res 127: 83−92. Disclosure statement: Stefan Leucht has received honoraria for consulting/advisory boards from Alkermes, Bristol-Myers-Squibb, EliLilly, Janssen, Johnson & Johnson, Medavante and Roche, and lecture honoraria from AstraZeneca, Bristol-Myers-Squibb, EliLilly, EssexPharma, Janssen, Johnson & Johnson, Lundbeck Institute, Pfizer and SanofiAventis. EliLilly has provided medication for a trial with SL as the primary investigator.
C.13. The past, present and future treatment of patients with schizophrenia − how far have we come?
[2] Moos, R.H., Moos, B.S., 2006 Rates and predictors of relapse after natural and treated remission from alcohol use disorders. Addiction 101, 212–222. [3] Gastfriend, D.R., et al., 2007 Reduction in heavy drinking as a treatment outcome in alcohol dependence. Journal of Substance Abuse Treatment 33, 71−80. Disclosure statement: Grants: Neurotech Honoraria: Eli Lilly, Lundbeck, Schering-Plough, Pfizer, Merck Serono Advisory boards: Merck Serono, Lundbeck, Schering-Plough, Teva
C.12.02 Engaging patients in the treatment of alcohol dependence − The role of reduction of alcohol consumption and “as-needed” dosing A. Gual1 ° 1 Hospital Clinic, Addictions unit, Barcelona, Spain Traditional methods for treating alcohol dependence have focused on total abstinence. However, many individuals with alcohol dependence are not able, or inclined, to achieve abstinence, resulting in a medical condition that is under-diagnosed and under-treated. In Europe, a small proportion (8.3%) of people diagnosed with alcohol dependence receive treatment [1]. Increasingly, there is an acceptance of reduction of alcohol consumption as part of a continuum of treatment goals for patients with alcohol dependence. Many national and international guidelines endorse reduction as a treatment paradigm. The option of reduction of alcohol consumption lowers the treatment barrier [2] and may help to close the treatment gap. Furthermore, patients may do better when enabled to choose, as opposed to being assigned, a treatment goal. Moreover, allowing patients to have a say in dosing regimens can be considered as a means to engaging patients in active and responsible management of their treatment, improving thereby patient adherence and compliance to treatment. These two aspects were incorporated in the recently completed Phase III program designed to assess the efficacy and safety of nalmefene. The experience with the approximately 2,000 patients enrolled in the studies contributes to prove the feasibility of reduction as an achievable treatment goal and “as needed” dosing in patients with alcohol dependence. In line with the recent changes in modern management of addictions, with patient centred approaches based on internal rather than external confrontation, negotiating treatment goals and dosing regimens are proposed as two valid options towards patient empowerment and therapeutic relationship facilitation. References [1] Alonso, J., et al., 2004 Use of mental health services in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl 420, 47−54. [2] Marlatt, G.A., Witkiewitz, K., 2002 Harm reduction approaches to alcohol use: Health promotion, prevention, and treatment. Addict Behav 27, 867–886. [3] Soyka, M., Rosner, S., 2010 Nalmefene for treatment of alcohol dependence. Expert Opin Investig Drugs 19 (11), 1451–1459. Disclosure statement: Grants: Lundbeck, FP7, SANCO Honoraria: Servier, Lundbeck Advisory boards: Lundbeck.
C.12.03 A potential new treatment for alcohol dependence: results from nalmefene phase III clinical program K. Mann1 ° 1 Central Institute of Mental Health Mannheim University of Heidelberg, Department for Addictive Behaviour, Mannheim, Germany Three multi-centre, double-blind, placebo-controlled Phase III studies, designed to assess the efficacy and safety of nalmefene
in reducing alcohol consumption, enrolled close to 2000 patients with alcohol dependence. Despite a long period (>10 years) of problem drinking, the vast majority of the alcohol-dependent patients included in the nalmefene clinical trials had not previously received any treatment for their condition, underlining the need for a new approach to treating these patients. In the two efficacy studies (ESENSE 1 and ESENSE 2), nalmefene was superior to placebo in reducing the number of heavy drinking days (HDDs, p < 0.05 in both studies) and total alcohol consumption (TAC, ESENSE 1, p < 0.05; ESENSE 2, p = 0.088) at Month 6. In the 1-year safety study (SENSE), nalmefene was superior to placebo (p < 0.05) in reducing the number of HDDs and TAC at the majority of the time points and at the end of the study, although not at Month 6. In all the studies, the effect of nalmefene was evident already at month one and was maintained throughout the treatment period. For all three studies, improvements in CGI scores and reductions in liver enzymes gamma-glutamyltransferase and alanine aminotransferase from baseline were larger in the nalmefene group compared to placebo throughout the study periods. The most frequent adverse events reported included dizziness, insomnia and nausea, and were mild and transient. The majority of these events had an onset within the first days after the first dose and decreased with treatment continuation. Disclosure statement: Grants: Alkermes, Lundbeck, McNeil, MundiPharma, Merck Sharp & Dohme Honoraria: Pfizer, Lundbeck, Alkermes & Desitin Advisory board/consultant: Pfizer, Lundbeck, Alkermes.
C.13. The past, present and future treatment of patients with schizophrenia − how far have we come? C.13.01 The effect of antipsychotic medication on brain structure in schizophrenia S. Frangou1 ° 1 Institute of Psychiatry King’s College London, Section of Neurobiology of Psychosis Department of Psychosis Studies, London, United Kingdom Antipsychotic medication represents the main therapeutic intervention for schizophrenia. The benefits of antipsychotic treatment in symptomatic control are well established. In contrast, evidence regarding their impact on brain structure is still accumulating. Neuroimaging studies have identified widespread brain anatomical changes in patients with schizophrenia. However, since the majority of patients participating in these studies were receiving treatment with antipsychotics, questions have arisen about the contribution of antipsychotic medication to the observed changes. We conducted a narrative review of gray matter structural changes associated with antipsychotic treatment, particularly the use of second generation antipsychotics (SGAs), and a quantitative voxel-based and region of interest meta-analysis of diffusion tensor imaging (DTI) studies (n = 40) in order to elucidate the effect of medication on white matter architecture. SGAs are associated with increased thalamic volume [1] while their effect on cortical gray matter is less clear; some studies suggest a preservative effect of SGAs on gray matter [2], while others do not [3]. Our quantitative meta-analysis of DTI studies in patients with schizophrenia found evidence for SGA treatment being associated
C.13. The past, present and future treatment of patients with schizophrenia − how far have we come? with normalization of DTI measures in the internal capsule, corpus callosum and the white matter of the right cingulate and superior temporal gyri. These results suggest that SGAs may normalize gray and white matter changes in patients with schizophrenia, although the corresponding microstructural changes responsible are unclear. The lack of longitudinal, within-subject designs is a major gap in the current literature. References [1] Tomelleri, L., Jogia, J., Perlini, C., et al. 2009 Brain structural changes associated with chronicity and antipsychotic treatment in schizophrenia. Eur Neuropsychopharmacol 19: 835–840. [2] Lieberman, J.A., Tollefson, G.D., Charles, C., et al. 2005 Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 62: 361–370. [3] Bora, E., Fornito, A., Radua, J., et al. 2011 Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis. Schizophr Res 127: 46−57. Disclosure statement: Sophia Frangou has served as consultant, advisor or speaker for Janssen-Cilag, Bristol-Myers-Squibb/Otsuka and Lundbeck.
C.13.02 Pharmacological and non-pharmacological therapies as integral parts for optimizing patient outcomes A. Schreiner1 ° 1 Janssen EMEA, Department of Medical and Scientific Affairs, Neuss, Germany The care of patients with schizophrenia has shifted from an institutionalized-based approach to one more centered in the community [1]. This approach includes social support and outreach schemes, often conducted by nurses and involving patients’ friends and families. In spite of this change many patients’ first experience of antipsychotic treatment still occurs in hospital. The issues faced in this setting and the treatment options available not only pose many questions for healthcare professionals, but impact on the success of subsequent community-based care. Indeed, balancing non-pharmacological treatments that support social rehabilitation with the need for continuous antipsychotic medication is vital to the management of integrated care in schizophrenia, and to ensuring successful transition from the inpatient to outpatient setting. As well as symptomatic control, treatment goals in the hospital setting frequently include addressing agitation and aggression. While intramuscular depot antipsychotics have been used, their associated side effects can contribute to a negative attitude towards injectable formulations leading many patients to discontinue treatment [2]. Nevertheless, it may be pertinent to consider a possible role for long-acting injectable (LAI) antipsychotics in this setting. Amongst the LAI antipsychotics available, paliperidone palmitate has been shown to offer a rapid onset of efficacy, with reduced risk of relapse compared with placebo in clinical trials, both of which are achieved with acceptable tolerability [3]. As such, LAI antipsychotics may have a role in the hospital setting with the potential for continuous treatment and optimum longer-term patient benefits. References [1] Kirkby, K.C., 2005 Social context and health consequences of the antipsychotics introduction. Ann Clin Psychiatry 17: 141–146. [2] Kasper, S., 2005 Treatment challenges in the acute hospital setting. World J Biol Psychiatry 6: 210–211. [3] Citrome, L., 2010 Paliperidone palmitate − review of the efficacy, safety and cost of a new second-generation depot antipsychotic medication. Int J Clin Pract 64: 216–239. Disclosure statement: Andreas Schreiner is a full-time employee of Janssen.
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C.13.03 Translating the evidence on the clinical benefits of antipsychotics for routine practice S. Leucht1 ° 1 Technische Universit¨at M¨unchen, Department of Psychiatry and Psychotherapy, Munich, Germany Advances in pharmacotherapy have given psychiatrists an increased number of options when selecting the most appropriate treatment for their patients with schizophrenia. Choosing between a number of antipsychotic medications that differ in their receptor binding profiles, formulation and pharmacokinetics is only a part of this selection process. Judging drugs’ effectiveness on the basis of data derived from different outcome parameters, including clinical efficacy, tolerability and patient functioning, whether from randomized controlled trials or naturalistic or observational studies may not be straightforward. In light of these factors, and the scarcity of active comparator trials, meta-analyses of both clinical trial and real-world study data can be instrumental in elucidating the clinical benefits of antipsychotic drugs, and help inform psychiatrists in their daily treatment decision-making. Evidence from meta-analyses has revealed that, compared with placebo, antipsychotics are highly efficacious in preventing relapse [1], both overall and in important subgroups such as first episode patients and stabilized patients. However, there is little long-term data addressing whether second-generation and firstgeneration antipsychotics differ in relapse prevention [2]. Data from large observational and mirror-image studies has helped to show injectable formulations to have superiority over oral formulations in preventing relapse. However, methodological issues (such as the exclusion of non-adherent patients) in some randomizedcontrolled trials may have reduced a potential superiority of depot antipsychotics [3]. By using evidence from large-scale meta-analyses, the impact of various antipsychotic treatment options on clinical practice and their day-to-day relevance for practicing psychiatrists can be better understood. References [1] Leucht, S. et al., 2009 How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 14: 429–447. [2] Leucht, S. et al., 2009 Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373: 31−41. [3] Leucht, C. et al., 2011 Oral versus depot antipsychotic drugs for schizophrenia − a critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res 127: 83−92. Disclosure statement: Stefan Leucht has received honoraria for consulting/advisory boards from Alkermes, Bristol-Myers-Squibb, EliLilly, Janssen, Johnson & Johnson, Medavante and Roche, and lecture honoraria from AstraZeneca, Bristol-Myers-Squibb, EliLilly, EssexPharma, Janssen, Johnson & Johnson, Lundbeck Institute, Pfizer and SanofiAventis. EliLilly has provided medication for a trial with SL as the primary investigator.